TW202413378A - Macrocycle compounds for the treatment of cancer - Google Patents

Abstract

The present invention relates to compounds of formula (I), , wherein R ¹to R ⁷, A ¹and A ²are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

Macrocyclic compounds for cancer treatment

The present invention relates to organic compounds useful for treatment and/or prevention in mammals, and in particular to the inhibition of KRAS mutants useful for the treatment of cancer.

RAS is one of the best-known oncogenes. Approximately 30% of human cancers contain mutations in the three most prominent members, KRAS, HRAS, and NRAS, making them the most common oncogenic drivers. KRAS mutations are often associated with a poor prognosis, especially in colorectal cancer, pancreatic cancer, and lung cancer. As the most commonly mutated RAS isoform, KRAS has been intensively studied in the past few years. Among the most common KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D, and G12V account for more than half of all K-RAS-driven cancers in colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). It is worth noting that among all KRAS-altered cancers (ovarian cancer, esophagogastric cancer, and uterine cancer), about 7% were also found to have KRAS wild-type expansion, ranking at the forefront of the alterations.

All RAS proteins belong to a family of small GTPase proteins that hydrolyze GTP to GDP. KRAS is structurally divided into an effector binding lobe, followed by an allosteric lobe and a carboxyl-terminal region responsible for membrane anchoring. The effector lobe contains the P-loop, switch I, and switch II regions. The switch I/II loop plays a key role in KRAS downstream signaling by mediating protein-protein interactions with effector proteins, such as RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway.

KRAS protein switches between inactive and active forms by binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son of Sevenless homolog 1 (SOS1) or GTPase activating proteins (GAPs), which are involved in catalyzing the exchange of GDP for GTP, thereby enhancing intrinsic GTPase activity or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted to active RAS-GTP, which directly binds to the RAF RAS binding domain (RAF ^RBD ), thereby recruiting the RAF kinase family from the cytoplasm to the membrane, where the two dimerize and become active. Activated RAF then undergoes a series of phosphorylation reactions on its downstream mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), and propagates growth signals. Among the RAF protein kinase family (three known isoforms ARAF, BRAF, CRAF/RAF1), BRAF is the most frequently mutated and remains the most potent MEK activator. Although individual RAS and RAF family members show different binding preferences, all RAFs have a conserved RBD for forward transmission of MAPK signaling, which is often used to characterize KRAS inhibition (such as the KRAS-BRAF ^RBD in this article). For KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift to the active KRAS form by impairing nucleotide hydrolysis or activating nucleotide exchange, thereby causing overactivation of the MAPK pathway and contributing to tumorigenesis.

Despite its recognized importance in cancer malignancies, persistent efforts have failed to develop approved treatments for KRAS mutant cancers until recently, when the first selective drug, AMG510, was rapidly approved as a second-line treatment for KRAS G12C-driven non-small cell lung cancer (NSCLC). However, clinically acquired resistance to KRAS G12C inhibitors emerges brutally with disease progression after approximately 6 months of treatment. All mutations converge to reactivate RAS-MAPK signaling, with secondary RAS mutants observed at oncogenic hotspots (e.g., G12/G13/Q61) and within the switch II pocket (e.g., H95, R68, and Y96); more than 85% of all cancers driven by KRAS mutants or wild-type expansions remain drug-deficient. In summary, the myriad escape mechanisms and various oncogenic alleles highlight the urgent medical need for additional KRAS therapeutics. Therefore, we have developed oral compounds that target and inhibit KRAS alleles for the treatment of KRAS mutant-driven cancers.

First-generation KRAS G12C inhibitors, such as Sotorosib and Adagrasib, that target the 'GDP bound off' form (RASOFF) of the KRAS G12C mutation have shown promising efficacy. Although this treatment has benefited many patients with activating KRAS mutations, almost all of the patients who initially benefit will eventually develop resistance through various mechanisms. An increasing number of KRAS G12C secondary mutation cases have been identified from patient samples, such as Y96D, R68S, H95D, H95Q, H95R, V8L (Tanaka et al., Cancer Discovery (2021), Awad et al., NEJM (2021), Ho et al., EJC (2021), Zhao et al., Nature (2021), Tsai et al., JCI (2022)), or from saturation-induced mutations (Siyu et al., PNAS (2022)) and ENU-induced mutations (Takamasa et al., J Thorac Oncol (2021)), which show resistance to KRAS(OFF) G12C inhibitors. Therefore, there is an unmet need to prevent the acquisition of one or more mutations in RAS that confer resistance to RAS(OFF) inhibitors.

The present invention relates to novel compounds of formula (I), (I), wherein R ¹ is , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidinyl or (C _1-6 alkyl)oximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridine, C _1-6 alkylpiperidinyl, halogen tetrahydroaziridine, halogen C _1-6 alkylamino, halogen C _{1-6 alkylaminotetrahydroaziridine, halogen C 1-6} alkylpiperidinyl _{, hydroxy(C 1-6 alkyl)piperidinyl or morpholinyl; R 2 is C 1-6 alkyl} ^; _R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is fluoroquinoline, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ^{1 is} thiazolyl; A ² is C _1-6 alkyl; provided that R ₃ and R ⁴ are not H at the same time; or a pharmaceutically acceptable salt _thereof .

The present invention also relates to its manufacture, to medicaments based on the compounds according to the present invention and their production, and to the use of compounds of formula (I) or (Ia) as KRAS inhibitors.

The compounds of formula (I) or (Ia) show good KRAS inhibitory effects on G12C, G12D and G12V. In another embodiment, the compounds of the present invention show excellent cancer cell inhibitory effects and human liver cell stability. In addition, the compounds of formula (I) or (Ia) also show good or improved cytotoxicity and solubility profiles. In addition, compared with the reference compound, the compounds of the present invention have excellent pharmacokinetic properties.

Definition

The term "C _1-6 alkyl" refers to a saturated, linear or branched alkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n -propyl, isopropyl, n-butyl, isobutyl , tertiary butyl, etc. Specific "C _1-6 alkyl" are methyl, ethyl and n- propyl.

The term "C _1-6 alkoxy" refers to C _1-6 alkyl-O-.

The term "C _1-6 alkylene" refers to a straight chain or branched chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of C _1-6 alkylene include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

The terms "halogen" and "halogen" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

The term "halogenated C _1-6 alkyl" refers to a C _{1-6 alkyl group in which at least one of the hydrogen atoms of the C 1-6 alkyl} group is replaced by the same or different halogen atoms (particularly, a fluorine atom). Examples of halogenated alkyl groups include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl.

The term " _C3-7 cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more common carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl or bicyclo[2.2.2]octyl.

The term "thiazolyl" refers to a divalent thiazolyl group.

The term "oxo" refers to a divalent oxygen atom =O.

The term "side oxygen imidazolidinyl" means .

The term "halogenated tetrahydroazabithyl" refers to a tetrahydroazabithyl group in which at least one of the hydrogen atoms of the tetrahydroazabithyl group has been replaced by the same or different halogen atoms, in particular, a fluorine atom. Examples of halogenated tetrahydroazabithyl groups include fluorotetrahydroazabithyl and difluorotetrahydroazabithyl.

The term "dimethylmethylene" means .

The term "protecting group" in the meaning conventionally associated with it in synthetic chemistry refers to a group that selectively blocks a reaction site in a multifunctional compound so that a chemical reaction can be selectively carried out at another unprotected reaction site. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups or hydroxyl protecting groups.

Those skilled in the art will appreciate that the following structures of compounds of formula (Ia) and (Ia') are identical, especially with respect to the chiral center: (Ia') (Ia)

The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid-added salt" means their pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthracene, benzoic acid, cinnamic acid, mandelic acid, enbolic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable alkaline additive salt" refers to pharmaceutically acceptable salts formed with organic bases or inorganic bases. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts. Salts derived from pharmaceutically acceptable nontoxic organic bases include salts of primary, di- and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trihydroxymethylaminomethane, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobrene, purines, piperidine, piperidine, N -ethylpiperidine and polyamine resins.

The term "pharmaceutically active metabolite" means a pharmacologically active product produced by in vivo metabolism of a specified compound or its salt. After entering the body, most drugs are substrates for chemical reactions that can change their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the present invention, change the way the drug is distributed in the body and secreted out of the body. However, in some cases, drug metabolism is required for therapeutic effect.

The term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, achieves the following effects: (i) treating or preventing a specific disease, condition or disorder described herein, (ii) reducing, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder described herein, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The therapeutically effective amount varies depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient to be administered to a mammal (e.g., a human) in need thereof.

The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inert excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent or lubricant used in formulating a pharmaceutical product.

KRAS Inhibitors

The present invention relates to (i) a compound of formula (I), (I), wherein R ¹ is , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidinyl or (C _1-6 alkyl)oximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridine, C _1-6 alkylpiperidinyl, halogen tetrahydroaziridine, halogen C _1-6 alkylamino, halogen C _{1-6 alkylaminotetrahydroaziridine, halogen C 1-6} alkylpiperidinyl _, hydroxy(C _1-6 alkyl)piperidinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C R ⁶ is C _1-6 alkoxy C _{1-6 alkyl} ; R ⁷ is fluoroquinoline, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ¹ is thiazolyl; A ² is C _1-6 alkylene; provided that R ³ and R ⁴ are not H at the _same time; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (ii) a compound of formula (Ia), (Ia), wherein R ¹ is , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidinyl or (C _1-6 alkyl)oximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridine, C _1-6 alkylpiperidinyl, halogen tetrahydroaziridine, halogen C _1-6 alkylamino, halogen C _{1-6 alkylaminotetrahydroaziridine, halogen C 1-6} alkylpiperidinyl _{, hydroxy(C 1-6 alkyl)piperidinyl or morpholinyl; R 2 is C 1-6 alkyl} ^; _R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C R ⁶ is C _1-6 alkoxy C _{1-6 alkyl} ; R ⁷ is fluoroquinoline, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ¹ is thiazolyl; A ² is C _1-6 alkylene; provided that R ³ and R ⁴ are not H at the _same time; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (iii) a compound of formula (I) or (Ia) as in (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R ¹ is ; wherein R ⁸ is C _1-6 alkyl; R ⁹ is C _1-6 alkylpiperidinyl, halogen C _1-6 alkylpiperidinyl or morpholinyl.

Another embodiment of the present invention is (iv) a compound of formula (I) or (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R ¹ is ; wherein R ⁸ is methyl; R ⁹ is 4-methylpiperidin-1-yl, 4-(2,2,2-trifluoroethyl)piperidin-1-yl or morpholinyl.

Another embodiment of the present invention is (v) a compound of formula (I) or (Ia) as defined in any one of (i) to (iv), wherein R ¹ is methyl-(4-methylpiperidin-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperidin-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino.

Another embodiment of the present invention is (vi) a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (v), wherein R ² is isopropyl.

Another embodiment of the present invention is (vii) a compound of formula (I) or (Ia) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein R ³ is H or fluorine.

Another embodiment of the present invention is (viii) a compound of formula (I) or (Ia) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R ³ is fluorine.

Another embodiment of the present invention is (ix) a compound of formula (I) or (Ia) according to any one of (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H or fluorine.

Another embodiment of the present invention is (x) a compound of formula (I) or (Ia) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H.

Another embodiment of the present invention is (xi) a compound of formula (I) or (Ia) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a halogen C _1-6 alkyl group.

Another embodiment of the present invention is (xii) a compound of formula (I) or (Ia) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is 2,2,2-trifluoroethyl.

Another embodiment of the present invention is (xiii) a compound of formula (I) or (Ia) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is 1-methoxyethyl.

Another embodiment of the present invention is (xiv) a compound of formula (I) or (Ia) according to any one of (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein R ⁷ is (halogen C _1-6 alkyl)piperidinyl.

Another embodiment of the present invention is (xv) a compound of formula (I) or (Ia) according to any one of (i) to (xiv), or a pharmaceutically acceptable salt thereof, wherein R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl.

Another embodiment of the present invention is (xvi) a compound of formula (I) or (Ia) according to any one of (i) to (xv), or a pharmaceutically acceptable salt thereof, wherein A ¹ is , where bond "a" is attached to the indole ring.

Another embodiment of the present invention is (xvii) a compound of formula (I) or (Ia) according to any one of (i) to (xvi), or a pharmaceutically acceptable salt thereof, wherein A ² is dimethylmethylene.

Another embodiment of the present invention is (xviii) a compound of formula (I) or (Ia) as (i) or (ii), wherein R ¹ is wherein R ⁸ is C _1-6 alkyl; R ⁹ is C _1-6 alkylpiperidinyl, halogen C _1-6 alkylpiperidinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is halogen; R ⁴ is H; R ⁵ is halogen C _1-6 alkyl; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is (halogen C _1-6 alkyl)piperidinyl; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is a _C1-6 alkylene group; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (xix) a compound of formula (I) or (Ia) such as (xviii), wherein R ¹ is methyl-(4-methylpiperidin-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperidin-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino; R ² is isopropyl; R ³ is fluorine; R ⁴ is H; R ⁵ is 2,2,2-trifluoroethyl; R ⁶ is (1S)-1-methoxyethyl; R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is dimethylmethylene; or a pharmaceutically acceptable salt thereof.

The present invention relates to a compound of formula (I) (i'), (I), wherein R ¹ is or (C _1-6 alkyl) pendioximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridinyl, halogenated tetrahydroaziridinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C _1-6 alkyl or halogenated C _1-6 alkyl; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is morpholinyl, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ¹ is thiazolyl; A ² is C _1-6 alkylene; provided that R ³ and R ⁴ are not H at the same time; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (ii') a compound of formula (Ia), (Ia), wherein R ¹ is or (C _1-6 alkyl) pendioximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridinyl, halogenated tetrahydroaziridinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C _1-6 alkyl or halogenated C _1-6 alkyl; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is morpholinyl, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ¹ is thiazolyl; A ² is C _1-6 alkylene; provided that R ³ and R ⁴ are not H at the same time; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (iii') a compound of formula (I) or (Ia) such as (i') or (ii'), or a pharmaceutically acceptable salt thereof, wherein R ¹ is ; wherein R ⁸ is a C _1-6 alkyl group; R ⁹ is a halogenated tetrahydroazide or morpholinyl group.

Another embodiment of the present invention is (iv') a compound of formula (I) or (Ia) as in any one of (i') to (iii'), or a pharmaceutically acceptable salt thereof, wherein R ¹ is ; wherein R ⁸ is methyl; and R ⁹ is 3,3-difluorotetrahydroazir-1-yl or morpholinyl.

Another embodiment of the present invention is (v') a compound of formula (I) or (Ia) according to any one of (i') to (iv'), wherein R ¹ is (3,3-difluorotetrahydroaziridine-1-carbonyl)-methyl-amino or methyl(oxoline-4-carbonyl)amino.

Another embodiment of the present invention is (vi') a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i') to (v'), wherein R ² is isopropyl.

Another embodiment of the present invention is (vii') a compound of formula (I) or (Ia) according to any one of (i') to (vi'), or a pharmaceutically acceptable salt thereof, wherein R ³ is H or fluorine.

Another embodiment of the present invention is (viii') a compound of formula (I) or (Ia) according to any one of (i') to (vii'), or a pharmaceutically acceptable salt thereof, wherein R ³ is fluorine.

Another embodiment of the present invention is (ix') a compound of formula (I) or (Ia) according to any one of (i') to (viii'), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H or fluorine.

Another embodiment of the present invention is (x') a compound of formula (I) or (Ia) of any one of (i') to (ix'), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H.

Another embodiment of the present invention is (xi') a compound of formula (I) or (Ia) according to any one of (i') to (x'), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is ethyl or 2,2,2-trifluoroethyl.

Another embodiment of the present invention is (xii') a compound of formula (I) or (Ia) according to any one of (i') to (xi'), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is 1-methoxyethyl.

Another embodiment of the present invention is (xiii') a compound of formula (I) or (Ia) as defined in any one of (i') to (xii'), or a pharmaceutically acceptable salt thereof, wherein R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl or morpholinyl.

Another embodiment of the present invention is (xiv') a compound of formula (I) or (Ia) according to any one of (i') to (xiii'), or a pharmaceutically acceptable salt thereof, wherein A ¹ is , where bond "a" is attached to the indole ring.

Another embodiment of the present invention is (xv') a compound of formula (I) or (Ia) according to any one of (i') to (xiv'), or a pharmaceutically acceptable salt thereof, wherein A ² is dimethylmethylene.

Another embodiment of the present invention is (xvi') a compound of formula (I) or (Ia) such as (i') or (ii'), wherein R ¹ is wherein R ⁸ is C _1-6 alkyl; R ⁹ is halogenated tetrahydroazir or morpholinyl; R ² is C _1-6 alkyl; R ³ is halogen; R ⁴ is H; R ⁵ is C _1-6 alkyl or halogenated C _1-6 alkyl; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is morpholinyl or (halogenated C _1-6 alkyl)piperidinyl; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is a _C1-6 alkylene group; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is (xvii') a compound of formula (I) or (Ia) such as (xvi'), wherein R ¹ is (3,3-difluorotetrahydroazir-1-carbonyl)-methyl-amino or methyl(morpholine-4-carbonyl)amino; R ² is isopropyl; R ³ is fluorine; R ⁴ is H; R ⁵ is ethyl or 2,2,2-trifluoroethyl; R ⁶ is (1S)-1-methoxyethyl; R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl or morpholine; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is dimethylmethylene; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a compound of formula (I) or (Ia) selected from the group consisting of (xx) 3-(dimethylamino) -N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-tetrahydroazol-1-carboxamide; 3-(dimethylamino) -N -[(1 S )-1-[[(7 S ,13 S )-25-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^{9,13.0 22,26} ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-tetrahydroazol-1-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; 3-(dimethylamino) -N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholine-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-tetrahydroazol-1-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholine-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-3,3-difluoro- N -methyl-tetrahydroazol-1-carboxamide; (2 S )- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butyramide; N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-20-(20 M )-[2-[(1 S )-1-methoxyethyl]-5-N-morpholine-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; 3-(dimethylamino) -N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-tetrahydroazol-1-carboxamide; (2 S )- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-[methyl(2,2,2-trifluoroethylaminomethyl)amino]butyramide; N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-3-(trifluoromethyl)tetrahydroazol-1-carboxamide; (2 S )- N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro- 1H -imidazo[5,1-c][1,4]oxadiazol-2-yl)butyramide; (3 R )- N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-pyridinyl-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminocarbonyl]-2-methyl-propyl]-3-hydroxy- N ,3-dimethyl-piperidin-1-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-25-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminocarbonyl]-2-methyl-propyl] -N -methyl-morpholine-4-carboxamide; N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N ,4-dimethyl-piperidin-1-carboxamide; and N -[(1 S )-1-[[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl] -N -methyl-4-(2,2,2-trifluoroethyl)piperidin-1-carboxamide; or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to (xxi) a method for preparing a compound as described in any one of (i) to (xix) or (i') to (xvii'), which comprises any of the following steps: a) in the presence of a coupling reagent and a base, reacting a compound of formula (II), (II) and acid (III), (III) to form a compound of formula (I); wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A ¹ and A ² are as defined in any one of (i) to (xix); the coupling reagent is T ₃ P, HATU, PyBOP or EDCI/HOBt; the base is TEA, DIEPA or DMAP.

Another embodiment of the present invention is (xxii) a compound or a pharmaceutically acceptable salt of any one of (i) to (xx) or (i') to (xvii') for use as a therapeutically active substance.

Another embodiment of the present invention is (xxiii) a pharmaceutical composition comprising a compound as described in any one of (i) to (xx) or (i') to (xvii') and a pharmaceutically acceptable excipient.

Another embodiment of the present invention is (xxiv) use of a compound as described in any one of (i) to (xx) or (i') to (xvii') for treating a KRAS G12C protein-related disease.

Another embodiment of the present invention is (xxv) use of a compound as described in any one of (i) to (xx) or (i') to (xvii') for treating diseases related to KRAS G12C, G12D and G12V proteins.

Another embodiment of the present invention is (xxvi) use of a compound as described in any one of (i) to (xx) or (i') to (xvii') for inhibiting the interaction between RAS and downstream effectors, wherein the downstream effectors are RAF and PI3K.

Another embodiment of the present invention is (xxvii) use of a compound as described in any one of (i) to (xx) or (i') to (xvii') for inhibiting propagation of oncogenic MAPK and PI3K signaling.

Another embodiment of the present invention is (xxviii) use of a compound of any one of (i) to (xx) or (i') to (xvii') for treating or preventing a cancer driven by a KRAS mutation, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

Another embodiment of the present invention is (xxix) use of a compound of any one of (i) to (xx) or (i') to (xvii') for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

Another embodiment of the present invention is (xxx) a compound or a pharmaceutically acceptable salt of any one of (i) to (xx) or (i') to (xvii'), for use in treating or preventing a cancer driven by a KRAS mutation, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

Another embodiment of the present invention is (xxxi) a compound or a pharmaceutically acceptable salt of any one of (i) to (xx) or (i') to (xvii'), for use in treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation of G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

Another embodiment of the present invention is (xxxii) use of a compound of any one of (i) to (xx) or (i') to (xvii') for the preparation of a medicament for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

Another embodiment of the present invention is (xxxiii) use of a compound of any one of (i) to (xx) or (i') to (xvii') for the preparation of a medicament for treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation of G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L.

Another embodiment of the present invention is (xxxiv) a method for treating or preventing KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xx) or (i') to (xvii').

Another embodiment of the present invention is (xxxv) a method of treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H, and F156L.

Another embodiment of the present invention is (xxxvi) a compound or a pharmaceutically acceptable salt of any one of (i) to (xx) or (i') to (xvii'), prepared according to the method of (xxi).

Pharmaceutical compositions and administration

Another embodiment provides pharmaceutical compositions or drugs comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, and methods of preparing such compositions and drugs using the compounds of the invention. In one embodiment, the compound of formula (I) can be formulated into a galenical administration form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration employed) at an appropriate pH at ambient temperature and at the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but in any case the preferred range is from about 3 to about 8. In one embodiment, the compound of formula (I) is formulated in ethyl acetate buffer (pH 5). In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

The compositions will be formulated, dosed, and administered in a manner consistent with good medical practice. In this context, factors to be considered include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to medical practitioners. An "effective amount" of the compound to be administered will be governed by these considerations and will be the minimum amount required to inhibit the interaction of mutant RAS (e.g., KRAS G12C) with RAF, thereby blocking oncogenic MAPK signaling. For example, such an amount may be below an amount that is toxic to normal cells or to the entire mammal.

In one example, the pharmaceutically effective amount of the compound of the present invention per dose administered parenterally will be in the range of about 0.1 mg/kg to 1000 mg/kg, alternatively in the range of about 0.1 mg/kg patient weight/day to 1000 mg/kg patient weight/day, with a typical initial range of 0.3 mg/kg/day to 15 mg/kg/day of the compound used. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain about 1 mg to about 1000 mg of the compound of the present invention.

The compounds of the present invention may be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired, for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention can be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients . Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, penetrants, lubricants, processing aids, coloring agents, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide a good presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or assist in the manufacture of the drug (i.e., medicament).

An example of a suitable oral dosage form is a tablet containing about 1 mg to 1000 mg of a compound of the present invention and about 1 mg to 1000 mg of anhydrous lactose, about 1 mg to 1000 mg of cross-linked sodium carboxymethyl cellulose, about 1 mg to 1000 mg of polyvinyl hydropyrrolidone (PVP) K30, and about 1 mg to 1000 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. An example of a spray formulation can be prepared by dissolving a compound of the invention (e.g., 5 mg to 400 mg) in a suitable buffer solution (e.g., phosphate buffer) and, if necessary, adding a tonicity agent (e.g., a salt such as sodium chloride). The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

Therefore, one embodiment includes a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt. In another embodiment, a pharmaceutical composition is included, which comprises a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating a cancer driven by a mutant KRAS. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating a cancer driven by a mutant KRAS.

The following compositions A and B show typical compositions of the present invention, but are merely representative of such compositions.

Composition A

The compound of the present invention itself can be used as the active ingredient of a tablet of the following composition in a known manner: Active ingredient per tablet 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropyl methylcellulose 20 mg 425 mg

Composition B

The compound of the present invention itself can be used as the active ingredient of a capsule of the following composition in a known manner: Active ingredient per capsule 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Indications and treatment methods

The compounds of the present invention induce a new binding pocket in KRAS by driving the formation of a high-affinity tri-complex between the KRAS protein and the ubiquitously expressed cyclophilin A (CYPA), and the compounds inhibit the interaction of KRAS with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention can be used to inhibit the propagation of oncogenic MAPK and PI3K signaling, reducing cell proliferation, particularly cancer cells. The compounds of the present invention can be used to terminate RAS signaling in cells expressing RAS mutations, such as pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, endometrial cancer, etc. driven by KRAS mutations. Alternatively, the compounds of the present invention can be used to terminate RAS signaling in malignant solid tumors, where the oncogenic effects of KRAS mutations are enhanced by dysregulation or mutation of effector pathways such as MAPK, PI3K-AKT-mTOR (mammalian target of rapamycin) driven signaling, and such compounds are used in targeted therapies for pancreatic cancer, colorectal cancer, non-small cell lung cancer, etc.

Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, an isomer or a pharmaceutically acceptable salt thereof.

synthesis

The compounds of the present invention can be prepared by any known means. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise specified, all substituents, in particular R ¹ to R ⁷ , A ¹ and A ² are as defined above. In addition, and unless otherwise expressly stated, all reactions, reaction conditions, abbreviations and symbols have the meanings familiar to those skilled in the art of organic chemistry.

A general synthetic route for preparing compounds of formula (I) is shown below.

plan 1

Compounds of formula II are synthesized as described in the procedures for intermediates A to J. Compounds of formula ( I) can be obtained by coupling reaction between acid ( III ) and compound of formula ( II ) using one or more coupling reagents (such as T ₃ P, HATU, PyBOP and EDCI/HOBt) in the presence of a base (such as TEA, DIEPA and DMAP).

The compounds of the present invention can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compound of formula ( I ) can be obtained by using the corresponding chiral starting materials according to the above process.

The present invention also relates to a method for preparing a compound of formula (I), comprising the following steps: a) reacting a compound of formula (II) in the presence of a base and a coupling reagent, (II) and acid (III), (III) to form a compound of formula (I); wherein in step a), the coupling reagent may be, for example, T ₃ P, HATU, PyBOP or EDCI/HOBt; the base may be, for example, TEA, DIEPA or DMAP. When prepared according to the above method, the compound of formula (I) or formula (Ia) is also an object of the present invention.

Examples

The present invention will be more fully understood by referring to the following examples, which, however, should not be construed as limiting the scope of the present invention.

Abbreviation

The present invention will be more fully understood by referring to the following examples, which, however, should not be construed as limiting the scope of the present invention.

The abbreviations used in this paper are as follows: ACN acetonitrile aq. aqueous BOC-L-valeric acid ( S )-2-((tert-butyloxycarbonyl)amino)-3-methylbutanoic acid Boc- N -Me-Val-OH N- (tert-butyloxycarbonyl) -N -methyl- L -valeric acid (Boc) _2O Di-tert-butyl dicarbonate ( R )-binap ( R )-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl _CDCl3 : deuterated chloroform CDI 1,1'-carbonyldiimidazole _CD3OD : deuterated methanol COMU (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-morpholinyl-carbonium hexafluorophosphate DIEPA: N, N -diethylpropylamine DIBAL-H Diisobutylaluminum hydroxide DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMP 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzimidoyl-3-(1 H )-one DMSO: dimethylsulfoxide EDCI: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc or EA: ethyl acetate FRET fluorescence resonance energy transfer HATU: (1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) hr(s): hours HPLC: high performance liquid chromatography HOBt: N -hydroxybenzotriazole H-VAL-OTBU HCl ( S )-tert-butyl-2-amino-3-methylbutyrate hydrochloride [Ir(OMe)(COD)] ₂ (1,5-cyclooctadiene)(methoxy)iridium(I) dimer LDA diisopropylamidolithium MS: (ESI): Mass spectrometry (electrochemical ionization) min(s) min MTBE tert-butyl methyl ether NMM N -methylmorpholine NaBH(OAc) ₃ -triacetoxysodium borohydride NMR: NMR NMO 4-methylmorpholine N -oxide obsd. obsd. Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl ₂ [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Preparative HPLC Preparative High Performance Liquid Chromatography PyBOP: Benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate RT or rt: room temperature sat. Saturated SFC Supercritical Fluid Chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TEA: Trimethylamine TMEDA Tetramethylethylenediamine TMSCF ₃ Trifluoromethyltrimethylsilane T ₃ P: Propylphosphonic anhydride

General experimental conditions

The intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12/25 column module. ii) ISCO Combo Flash Chromatography Instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40 µm to 60 µm; ii) CAS Registry No.: Silica gel: 63231-67-4, particle size: 47 μm to 60 μm silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC on reverse phase columns using XBridge ^™ Prep-C18 (5 µm, OBD™ 30 × 100 mm) columns, SunFire ^™ Prep-C18 (5 µm, OBD ^™ 30 × 100 mm) columns, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and water containing 0.1% ammonium hydroxide; acetonitrile and water containing 0.1% FA or acetonitrile and water containing 0.1% TFA). or Gilson-281 purification system (pump 322, detector: UV 156, solvent system: acetonitrile and water containing 0.05% ammonium hydroxide; acetonitrile and water containing 0.225% FA; acetonitrile and water containing 0.05% HCl; acetonitrile and water containing 0.075% TFA; or acetonitrile and water).

For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm) or AD (10 µm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO ₂ and IPA (IPA containing 0.5% TEA) or CO ₂ and MeOH (MeOH containing 0.1% NH ₃ ∙H ₂ O), back pressure 100 bar, detection UV @ 254 or 220 nm.

LC/MS spectra of the compounds were obtained using LC/MS (Waters ^TM Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ) with the following LC/MS conditions (run time 3 or 1.5 min): Acidic conditions I: A: 0.1% TFA in H ₂ O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H ₂ O; B: 0.01875% TFA in acetonitrile; Alkaline conditions I: A: 0.1% NH ₃ ·H ₂ O in H ₂ O; B: acetonitrile; Alkaline conditions II: A: 0.025% NH ₃ ·H ₂ O in H _{2 O} O; B: acetonitrile; Neutral conditions: A: H ₂ O; B: acetonitrile. Mass spectra (MS): Usually only ions indicating the mass of the parent nucleus are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (MH) ⁺ .

NMR spectra were acquired using a Bruker Avance 400 MHz or 500 MHz.

Microwave-assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under argon or nitrogen pressure. Reagents were used as received from commercial suppliers without further purification unless otherwise specified.

Preparation Example

The following examples are intended to illustrate the meaning of the present invention, but should not be construed as limiting the meaning of the present invention:

Preparation of intermediates

Intermediate A

1-[6-[(1 S )-1- methoxyethyl ] -5-(4,4,5,5 - tetramethyl -1,3,2- dioxaborolan -2- yl )-3- pyridinyl ]-4- methyl - piperidin

The title intermediate A was prepared according to the following procedure:

Steps 1 ：Preparation 3- bromine -2-[(1 S )-1- Methoxyethyl ]-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Pyridine (compound A2 ）

To a solution of 3-bromo-2-[( 1S )-1-methoxyethyl]pyridine (Compound A1 , 2.0 g, 9.26 mmol) and bis(pinacol)borate (3.5 g, 13.9 mmol) in THF (30 mL) was added 4,4'-di-tert-butyl-2,2'-bipyridine (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)] ₂ (306.3 mg, 0.460 mmol). The mixture was stirred at 75°C under _N2 protection for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/PE: 0-20%) to give 3-bromo-2-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A2 , 2.4 g) as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ ppm 8.91 (d, J = 1.4 Hz, 1 H), 8.21 (d, J = 1.4 Hz, 1 H), 4.95 (q, J = 6.5 Hz, 1 H), 3.30 (s, 3 H), 1.49 (d, J = 6.5 Hz, 3 H), 1.35 (s, 12 H).

Steps 2 ：Preparation 3- bromine -5- iodine -2-[(1 S )-1- Methoxyethyl ] Pyridine (compound A3 ）

To a solution of 3-bromo-2-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A2 , 2.5 g, 7.3 mmol) in ACN (40 mL) was added N-iodosuccinimide (4.1 g, 18.27 mmol). The mixture was stirred at 90 °C under _N2 protection for ₄₀ hours. The reaction was quenched with saturated _Na2SO3 solution (40 mL) and the reaction mixture was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (50 mL), filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (EA/PE: 0-20%) to obtain 3-bromo-5-iodo-2-[( 1S )-1-methoxyethyl]pyridine (Compound A3 , 660 mg) as a yellow oil. MS Calcd. 342 (MH ⁺ ), Found 341.8 (MH ⁺ ).

Steps 3 ：Preparation 4-[5- bromine -6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound A5 ）

To a solution of 3-bromo-5-iodo-2-[( 1S )-1-methoxyethyl]pyridine (Compound A3 , 660 mg, 1.9 mmol) and 1-Cbz-piperidinium (Compound A4 , 425.1 mg, 1.9 mmol) in toluene (10 mL) was added cesium carbonate (1.6 g, 4.83 mmol), ( R )-BINAP (60.1 mg, 0.1 mmol) and palladium (II) acetate (43.3 mg, 0.19 mmol). The mixture was stirred at 100°C under _N2 protection for 12 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (EA/PE: 0-50%) to obtain benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylate (Compound A5 , 740 mg) as a yellow solid. MS calculated value 434.1 (MH ⁺ ), found value 434.1 (MH ⁺ ).

Steps 4 ：Preparation 1-[6-[(1 S )-1- Methoxyethyl ]-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-3- Pyridyl ]-4- methyl - Piperidone 𠯤 (Intermediate A ）

To a solution of benzyl 4-[5-bromo-6-[( 1S )-1-methoxyethyl]-3-pyridinyl]piperidinium-1-carboxylate (Compound A5 , 740 mg, 1.7 mmol) and bis(pinacol)borate (519.2 mg, 2.04 mmol) in toluene (12 mL) was added KOAc (418.0 mg, 4.26 mmol) and Pd(dppf) _Cl2 (124.7 mg, 0.170 mmol). The reaction mixture was stirred at 90°C under _N2 protection for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to give 1-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]-4-methyl-piperidinium (Intermediate A , 470 mg) as a brown solid. MS Calcd. 482.3 (MH ⁺ ), Found 482.2 (MH ⁺ ).

Intermediate B

( 3S )-1-[( 2S )-3-(4- bromothiazol -2- yl )-2-( tributyloxycarbonylamino ) propionyl ] hexahydrothiazol -3- carboxylic acid methyl ester

Intermediate B was prepared according to the following process:

Steps 1 ：Preparation (4- Bromothiazol -2- base ) Methanol (compound B2 ）

To a solution of 4-bromothiazole-2-carboxaldehyde (Compound B1 , 6.0 g, 31.25 mmol) in methanol (70 mL) at 0°C was added sodium borohydride (1.7 g, 46.87 mmol). The mixture was stirred at 25°C for 1 hour. The reaction was quenched with water (300 mL) at 0°C, and the reaction mixture was extracted with ethyl acetate (200 mL, three times). The combined organic phases were washed with brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give (4-bromothiazol-2-yl)methanol (Compound B2 , 6 g) as a colorless oil.

Steps 2 ：Preparation 4- bromine -2-( Bromomethyl ) Thiazole (compound B3 ）

To a solution of (4-bromothiazol-2-yl)methanol (Compound B2 , 6.0 g, 30.92 mmol) in DCM (80 mL) at 0°C was added _CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol). After stirring at 25°C for 1 hour, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate (0-10%) in petroleum ether to give (4-bromothiazol-2-yl)methanol (Compound B3 , 6.0 g) as a yellow oil. MS calculated value 255.9 (MH ⁺ ), found value 255.9 (MH ⁺ ).

Steps 3 ：Preparation 4- bromine -2-[[(2 S ,5 R )-5- Isopropyl -3,6- Dimethoxy -2,5- Pyridine 𠯤 -2- base ] methyl ] Thiazole (compound B5 ）

To a mixture of ( R )-2,5-dihydro-3,6-dimethoxy-2-isopropylpyridine (Compound B4 , 4.3 g, 23.45 mmol) in THF (60 mL) was slowly added n-butyl lithium (10 mL, 25.22 mmol, 2.5 M) at -78°C. After the addition, the mixture was stirred at -78°C for 0.5 hours. 4-Bromo-2-(bromomethyl)thiazole (Compound B3 , 5.4 g, 21.02 mmol) was added to the above mixture at -78°C, which was stirred for another hour. The reaction was quenched with saturated _NH4Cl solution (100 mL) and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse phase chromatography to give 4-bromo-2-[[( 2S , 5R )-5-isopropyl-3,6-dimethoxy-2,5-dihydropyridin-2-yl]methyl]thiazole (Compound B5 , 3.6 g) as a yellow oil. MS Calcd. 360 (MH ⁺ ), Found 359.9 (MH ⁺ ).

Steps 4 ：Preparation (2 S )-2- Amine -3-(4- Bromothiazol -2- base ) Methyl propionate (compound B6 ）

To a solution of 4-bromo-2-[[( 2S , 5R )-5-isopropyl-3,6-dimethoxy-2,5-dihydropyridin-2-yl]methyl]thiazole (Compound B5 , 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 h. The mixture was alkalized by saturated _NaHCO3 solution until pH = 8. The mixture was extracted with EtOAc (80 mL, six times). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give ( 2S )-methyl 2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound B6 , 3.1 g) as a yellow oil. MS calculated value 264.9 (MH ⁺ ), found value 264.9 (MH ⁺ ).

Steps 5 ：Preparation (2 S )-3-(4- Bromothiazol -2- base )-2-( Tertiary Butoxycarbonylamino ) Methyl propionate (compound B7 ）

To a solution of methyl ( 2S )-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound B6 , 3.1 g, 11.69 mmol) in DCM (40 mL) were added triethylamine (2.9 g, 29.23 mmol) and (Boc) _2O (3.8 g, 17.54 mmol). After stirring at 30°C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate (0-30%) in petroleum ether to give methyl ( 2S )-3-(4-bromothiazol-2-yl)-2-(tributyloxycarbonylamino)propanoate (Compound B7 , 3.2 g) as a yellow oil. MS calcd. 387 (MNa ⁺ ), found 386.9 (MNa ⁺ ).

Steps 6 ：Preparation (2 S )-3-(4- Bromothiazol -2- base )-2-( Tertiary Butoxycarbonylamino ) Propionic acid (compound B8 ）

To a solution of ( 2S )-3-(4-bromothiazol-2-yl)-2-(tri-butyloxycarbonylamino)propanoic acid methyl ester (Compound B7 , 3.2 g, 8.76 mmol) in THF (30 mL) methanol (2 mL) and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After stirring at 25°C for 1 hour, the reaction mixture was acidified by 1 M HCl solution until pH = 5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain ( 2S )-3-(4-bromothiazol-2-yl)-2-( tert -butyloxycarbonylamino)propanoic acid (Compound B8 , 3.1 g) as a yellow oil. MS calculated value 373 (MNa ⁺ ), found value 372.9 (MNa ⁺ ).

Steps 7 ：Preparation (3 S )-1-[(2 S )-3-(4- Bromothiazol -2- base )-2-( Level 3 Butoxycarbonylamino ) Propionyl ] Hexahydro 𠯤 -3- Methyl formate (intermediate B ）

To a solution of ( 2S )-3-(4-bromothiazol-2-yl)-2-(t-butyloxycarbonylamino)propanoic acid (Compound B8 , 3.1 g, 8.83 mmol) in DCM (50 mL) was added (3S)-methyl hexahydrothiazol-3-carboxylate hydrochloride (Compound B9 , 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-hydroxybenzotriazole (238.5 mg, 1.77 mmol) and NMM (9.92 mL, 88.26 mmol) at 0°C. After stirring at 25°C for 1 hour, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, three times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate (10-30%) in petroleum ether to give ( 3S )-1-[( 2S )-3-(4-bromothiazol-2-yl)-2-(tert-butyloxycarbonylamino)propanoyl]hexahydrothiazol-3-carboxylic acid methyl ester (Intermediate B , 2.4 g). MS calculated value 477 (MH ⁺ ), found value 476.9 (MH ⁺ ).

Intermediate C

(7 S ,13 S )-7- amino -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4- methylpiperidin - 1- yl )-3- pyridinyl ]-17,17- dimethyl -21-(2,2,2- trifluoroethyl )-15- oxa- 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene -8,14- dione

The title intermediate C was prepared according to the following scheme:

Steps 1 ：Preparation 1-(5- bromine -6- fluorine -1 H - Indole -3- base )-3-(( Tertiary butyldiphenylsilane ) Oxygen )-2,2- Dimethylpropane -1- Ketone (compound C3 ）

To a mixture of 3-((tributyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (Compound C1 , 35.0 g, 116.8 mmol) in DCM (400 mL) at 0°C was slowly added a solution of _SnCl4 (97.2 mL, 121.5 mmol). After the mixture was stirred at -40°C for 0.5 h, 5-bromo-6-fluoro- 1H -indole (Compound C2 , 25.0 g, 116.8 mmol) in DCM (200 mL) was added dropwise, and the mixture was stirred at -40°C for another 15 min. After the reaction was completed, it was quenched with saturated aqueous _NaHCO3 solution (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layers were washed with brine (700 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with a solution (100 mL, petroleum ether: ethyl acetate = 8:1) and filtered. The filter cake was dried in vacuo to give 1-(5-bromo-6-fluoro- 1H -indol-3-yl)-3-((tributyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (Compound C3 , 50.0 g) as a yellow solid. MS Calculated 552.1 (MH ⁺ ), Found 552.1 (MH ⁺ ).

Steps 2 ：Preparation [3-(5- bromine -6- fluorine -1 H - Indole -3- base )-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound C4 ）

To a mixture of 1-(5-bromo-6-fluoro- 1H -indol-3-yl)-3-((tributyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (Compound C3 , 50.0 g, 90.49 mmol) in THF (600 mL) was added _LiBH4 (48.4 mL, 193.49 mmol, 4 M in THF) dropwise at 0°C. The mixture was stirred at 70°C under nitrogen atmosphere for 24 hours. After the reaction was completed, it was quenched by slowly adding water (600 mL) at 0°C, and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layers were washed with brine (600 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc in PE = 20% ~ 33%) to give [3-(5-bromo-6-fluoro- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C4 , 46.0 g) as a white solid. MS calculated value 538.1 (MH ⁺ ), found value 538.2 (MH ⁺ ).

Steps 3 ：Preparation [3-(5- bromine -6- fluorine -2- iodine -1 H - Indole -3- base )-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound C5 ）

To a mixture of [3-(5-bromo-6-fluoro- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C4 , 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in THF (400 mL) at 0°C was added silver trifluoromethanesulfonate (20.3 g, 78.88 mmol). The mixture was stirred at 0°C for 10 _minutes . After the reaction was completed, it was quenched by saturated _Na2SO3 aqueous solution (400 mL) and EtOAc (400 mL) and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over _{Na2SO4 ,} filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc in PE = 0% ~ 2.5%) to give [3-(5-bromo-6-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C5 , 43.0 g) as a yellow solid. MS Calcd. 664.0 (MH ⁺ ), Found 664.1 (MH ⁺ ).

Steps 4 ：Preparation 4-[5-[5- bromine -3-[3-[ Tertiary Butyl ( Diphenyl ) Silane ] Oxygen -2,2- Dimethyl - Propyl ]-6- fluorine -1 H - Indole -2- base ]-6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound C6 ）

To a mixture of [3-(5-bromo-6-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C5 , 16.7 g, 25.13 mmol) and 4-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]piperidin-1-carboxylic acid benzyl ester (Intermediate A , 16.7 g, 34.69 mmol) in a mixed solution of 1,4-dioxane (270 mL)/toluene (90 mL)/water (90 mL) were added potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf) _Cl2 (920 mg, 1.26 mmol). The mixture was stirred at 70°C for 12 hours under nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc in PE = 20% ~ 50%) to give 4-[5-[5-bromo-3-[3-[tributyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro- 1H -indol-2-yl]-6-[( 1S )-1-methoxyethyl]-3-pyridyl]piperidinium-1-carboxylate (Compound C6 , 19.5 g) as a white solid. MS Calculated 891.3 (MH ⁺ ), Found 891.3 (MH ⁺ ).

Steps 5 ：Preparation 4-[(5 M )-5-[5- bromine -3-[3-[ Tertiary Butyl ( Diphenyl ) Silane ] Oxygen -2,2- Dimethyl - Propyl ]-6- fluorine -1-(2,2,2- Trifluoroethyl ) Indole -2- base ]-6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound C7 ）

To a solution of 4-[5-[5-bromo-3-[3-[tributyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro- 1H -indol-2-yl]-6-[( 1S )-1-methoxyethyl]-3-pyridinyl]piperidinium-1-carboxylate (Compound C6 , 14.5 g, 16.26 mmol) and _Cs2CO3 ( _15.9 g, 48.77 mmol) in DMF (200 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) dropwise at 0°C, and the mixture was stirred at 20°C for 12 hours. After the reaction was completed, EtOAc (70 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (100 mL, four times), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography to obtain 4-[(5 M )-5-[5-bromo-3-[3-[tributyl(diphenyl)silanyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidinium-1-carboxylic acid benzyl ester (Compound C7 , 8.0 g, eluted faster) as a yellow oil. MS calcd. 973.3 (MH ⁺ ), found 973.2 (MH ⁺ ).

Steps 6 ：Preparation 4-[(5 M )-5-[5- bromine -6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-1-(2,2,2- Trifluoroethyl ) Indole -2- base ]-6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound C8 ）

To a solution of benzyl 4-[(5 M )-5-[5-bromo-3-[3-[tributyl(diphenyl)silanyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylate (Compound C7 , 10.5 g, 10.78 mmol) in DMF (130 mL) was added cesium fluoride (8.2 g, 53.9 mmol), and the mixture was stirred at 60° C. for 24 hours. After the reaction was completed, EtOAc (100 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (80 mL, three times), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (EtOAc in PE = 25% ~ 66%) to obtain 4-[(5 M )-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidinium-1-carboxylic acid benzyl ester (Compound C8 , 6.5 g) as a yellow solid. MS calcd. 735.2 (MH ⁺ ), found 735.1 (MH ⁺ ).

Steps 7 ：Preparation 4-[(5 M )-5-[6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-1-(2,2,2- Trifluoroethyl ) Indole -2- base ]-6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound C9 ）

To a solution of benzyl 4-[(5 M )-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylate (Compound C8 , 5.4 g), bis(pinacol)borate (2.8 g, 11.01 mmol) and potassium acetate (1.2 mL, 18.35 mmol) in toluene (70 mL) was added Pd(dppf)Cl ₂ (537.1 mg, 0.73 mmol). The mixture was degassed and purged with nitrogen atmosphere three times, and the mixture was stirred at 90° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (EtOAc in PE = 25% ~ 66%) to give 4-[(5 M )-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylic acid benzyl ester (Compound C9 , 5.2 g) as a yellow oil. MS calcd. 783.3 (MH ⁺ ), found 783.3 (MH ⁺ ).

Steps 8 ：Preparation (3 S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4- Benzyloxycarbonylpiperidin 𠯤 -1- base )-2-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ]-6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-1-(2,2,2- Trifluoroethyl ) Indole -5- base ] Thiazole -2- base ]-2-( Tertiary Butoxycarbonylamino )- Propionyl ] Hexahydro 𠯤 -3- Methyl formate (compound C10 ）

Under nitrogen atmosphere, (3 S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-(tributyloxycarbonylamino)propionyl]hexahydrothiazol-3-carboxylic acid methyl ester (Intermediate B , 2.7 g, 5.69 mmol), 4-[(5 M )-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridyl]piperidin-1-carboxylic acid benzyl ester (Compound C9 , 4.9 g, 6.32 mmol) in toluene (60 To a mixture of 4-nitropropene (20 mL)/1,4-dioxane (20 mL)/water (20 mL) was added K ₃ PO ₄ (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl ₂ (412.2 mg, 0.63 mmol). The mixture was stirred at 70° C. for 12 hours. After the reaction was completed, the mixture was concentrated in vacuo to obtain a residue. The residue was purified by silica gel column (EtOAc in PE = 10% ~ 75%) to give ( 3S )-1-[( 2S )-3-[4-[( 2M )-2-[5-(4-benzyloxycarbonylpiperidin-1-yl)-2-[( 1S )-1-methoxyethyl]-3-pyridinyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tributyloxycarbonylamino)-propionyl]hexahydrothiazol-3-carboxylic acid methyl ester (Compound C10 , 3.6 g) as a brown solid. MS calcd. 1053.4 (MH ⁺ ), found 1053.3 (MH ⁺ ).

Steps 9 ：Preparation (3 S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4- Benzyloxycarbonylpiperidin 𠯤 -1- base )-2-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ]-6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-1-(2,2,2- Trifluoroethyl ) Indole -5- base ] Thiazole -2- base ]-2-( Tertiary Butoxycarbonylamino ) Propionyl ] Hexahydro 𠯤 -3- Formic acid (compound C11 ）

To a solution of ( 3S )-1-[( 2S )-3-[4-[( 2M )-2-[5-(4-benzyloxycarbonylpiperidin-1-yl)-2-[( 1S )-1-methoxyethyl]-3-pyridinyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tributyloxycarbonylamino)-propionyl]hexahydrothiazol-3-carboxylic acid methyl ester (Compound C10 , 3.6 g, 3.42 mmol) in DCE (50 mL) was added trimethyltin hydroxide (2.4 g, 13.67 mmol), and the mixture was stirred at 60 °C for 12 h. After the reaction was complete, EtOAc (80 mL) and water (60 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give (3 S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperidin-1-yl)-2-[(1 S )-1-methoxyethyl]-3-pyridinyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tributyloxycarbonylamino)propanoyl]hexahydrothiazol-3-carboxylic acid (Compound C11 , 4.3 g) as a brown solid. MS calcd. 1039.4 (MH ⁺ ), found 1039.2 (MH ⁺ ).

Steps 10 ：Preparation 4-[5-[(7 S ,13 S )-7-( Tertiary Butoxycarbonylamino )-twenty four- fluorine -17,17- Dimethyl -8,14- Dioxygen -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -(20 M )-20- base ]-6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Piperidone 𠯤 -1- Benzyl formate (compound C12 ）

To a mixture of (3 S )-1-[(2 S )-3-[4-[(2 M )-2-[5-(4-benzyloxycarbonylpiperidin-1-yl)-2-[(1 S )-1-methoxyethyl]-3-pyridinyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tributyloxycarbonylamino)-propionyl]hexahydrothiazol-3-carboxylic acid (Compound C11 , 4.3 g, 4.14 mmol) in DCM (430 mL) at 0° C. was added DIEA (14.4 mL, 82.76 mmol), EDCI (11.9 g, 62.07 mmol) and 1-hydroxybenzotriazole (1.4 g, 10.35 mmol). The mixture was stirred at 15 °C for 12 hours. After the reaction was completed, the mixture was concentrated in vacuo, then diluted with water (80 mL) and extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc in PE = 25% ~ 66%) to obtain 4-[5-[(7 S ,13 S )-7-(tributyloxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-(20 M )-20-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylic acid benzyl ester (Compound C12 , 3.1 g). MS calcd. 1021.4 (MH ⁺ ), found 1021.2 (MH ⁺ ).

Steps 11 ：Preparation N -[(7 S ,13 S )-24- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-(4- Methylpiperidone 𠯤 -1- base )-3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Tributyl carbamate (compound C13 ）

4-[5-[(7 S ,13 S )-7-(tributyloxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-(20 M )-20-yl]-6-[(1 S )-1-methoxyethyl]-3-pyridinyl]piperidin-1-carboxylic acid benzyl ester (Compound C12 , 3.1 g, 3.04 mmol) and aqueous formaldehyde solution (775.0 To a mixture of 2.79 g, 3.97 mmol) in methanol (150 mL) was added Pd(OH) ₂ on activated carbon (2.79 g, 3.97 mmol). The mixture was degassed and purged with H ₂ three times. The mixture was hydrogenated at 30 °C for 18 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to give N -[( 7S , 13S )-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^{2,5.1 9,13.0 22,26} ]Octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamic acid tributyl ester (Compound C13 , 2.6 g). MS calculated value 901.3 (MH ⁺ ), found value 901.3 (MH ⁺ ).

Steps 12 ：Preparation (7 S ,13 S )-7- Amine -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-(4- Methylpiperidone 𠯤 -1- base )-3- Pyridyl ]-17,17- Dimethyl -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -8,14- Diketone (intermediate C ）

To tributyl N -[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound C13 , 2.6 g, 2.89 mmol) in DCM (18 mL) To the mixture was added TFA (14.0 mL, 181.72 mmol). The mixture was stirred at 15°C for 0.5 h. After the reaction was completed, the mixture was concentrated in vacuo and diluted with saturated NaHCO ₃ (30 mL), and extracted with EtOAc (30 mL, three times). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate C , 2.0 g), which was used directly in the next step. MS calculated value 801.3 (MH ⁺ ), found value 801.2 (MH ⁺ )

Intermediate D

(7 S ,13 S )-7- amino -21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4 -methylpiperidin - 1- yl )-3 - pyridinyl ]-17,17 -dimethyl -15- oxa- 4 -thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene- 8,14 - dione

Analogously to the preparation of Intermediate C , the title compound was prepared by using iodoethane instead of 2,2,2-trifluoroethyl triflate.

Intermediate E

(7 S ,13 S )-7- amino -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin - 1- yl ]-3- pyridinyl ]-17,17- dimethyl -21-(2,2,2 -trifluoroethyl )-15- oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene- 8,14- dione

The compound was prepared according to the following scheme:

Steps 1 ：Preparation 1-[5- bromine -6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ]-4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 (Compound E2 ).

To a mixture of 3-bromo-5-iodo-2-[( 1S )-1-methoxyethyl]pyridine (Compound A3 , 2.03 g, 5.95 mmol) and 1-(2,2,2-trifluoroethyl)piperidinium (Compound E1 , 1.0 g, 5.95 mmol) in toluene (15 mL) were added _Cs2CO3 ( _4.85 g, 14.88 mmol), ( R )-binap (92.6 mg, 0.15 mmol) and Pd(OAc) ₂ (66.8 mg, 0.3 mmol). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 100°C under nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain 1-[5-bromo-6-[( 1S )-1-methoxyethyl]-3-pyridinyl]-4-(2,2,2-trifluoroethyl)piperidinium (Compound E2 , 2.0 g) as a yellow oil. MS calculated value 382.2 (MH ⁺ ), found value 382.1 (MH ⁺ ).

Steps 2 : 1-[6-[(1 S )-1- Methoxyethyl ]-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-3- Pyridyl ]-4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 (Compound E3 ).

To a solution of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridinyl]-4-(2,2,2-trifluoroethyl)piperidinium (Compound E2 , 3.2 g, 8.37 mmol), bis(pinacol)borate (3.19 g, 12.56 mmol) and KOAc (2.1 g, 20.93 mmol) in toluene (50 mL) was added Pd(dppf)Cl ₂ (306.3 mg, 0.42 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue, which was purified by reverse phase column to obtain 1-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]-4-(2,2,2-trifluoroethyl)piperidinium (Compound E3 , 1.9 g) as a yellow gum. MS calculated value 430.2 (MH ⁺ ), found value 348.4 (MC ₆ H ₁₀ +H ⁺ ).

Steps 3 ：Preparation [3-[5- bromine -6- fluorine -2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1 H - Indole -3- base ]-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound E4 ).

To a solution of 1-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]-4-(2,2,2-trifluoroethyl)piperidinium (Compound E3 , 1.9 g, 4.41 mmol), [3-(5-bromo-6-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C5 , 2.1 g, 3.15 mmol) in _1,4 -dioxane (24 mL), water (8 mL) and toluene (8 mL) were added _K3PO4 (2.1 g, 9.5 mmol) and Pd(dppf) _Cl2 (231 mg, 0.37 mmol). The mixture was degassed by bubbling nitrogen for 2 min, and the reaction mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (EtOAc in PE: 30% - 60%) to give [3-[5-bromo-6-fluoro-2-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl] -1H -indol-3-yl]-2,2-dimethyl-propyloxy]-tributyl-diphenyl-silane (Compound E4 , 960.0 mg) as a yellow gum. MS calcd. 839.3 (MH ⁺ ), found 839.3 (MH ⁺ ).

Steps 4 ：Preparation [3-[5- bromine -6- fluorine -(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1-(2,2,2- Trifluoroethyl ) Indole -3- base ]-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound E5 ).

To a solution of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl] -1H -indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound E4 , 1 g, 1.14 _mmol ) in DMF (35 mL) was added _Cs2CO3 (1.1 g, 3.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.63 mmol) at 0°C. After stirring at 20°C for 15 h, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL, three times). The combined organics were washed with brine (50 mL, three times), dried over _{Na2SO4 ,} filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography (EtOAc in PE: 30% - 40%) to give [3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propyloxy]-tributyl-diphenyl-silane as a white solid (Compound E5 , 640.0 mg, 0.69 mmol, eluted faster). MS calcd. 921.3 (MH ⁺ ), found 921.4 (MH ⁺ ).

Steps 5 ：Preparation 3-[5- bromine -6- fluorine -(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1-(2,2,2- Trifluoroethyl ) Indole -3- base ]-2,2- Dimethyl - C -1- Alcohol (compound E6 ).

To a solution of [3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound E5 , 640.0 mg, 0.69 mmol) in DMF (7 mL) was added cesium fluoride (421.8 mg, 2.78 mmol). The mixture was stirred at 60° C. for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (EtOAc in PE: 30% - 60%) to give 3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E6 , 360.0 mg) as a yellow oil. MS Calcd. 683.2 (MH ⁺ ), Found 683.1 (MH ⁺ ).

Steps 6 ：Preparation 3-[5- bromine -6- fluorine -(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1-(2,2,2- Trifluoroethyl ) Indole -3- base ]-2,2- Dimethyl - C -1- Alcohol (compound E7 ).

To a solution of 3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E6 , 360.0 mg, 0.53 mmol), bis(pinacol)borate (200.6 mg, 0.79 mmol) in toluene (6 mL) was added potassium acetate (129 mg, 1.32 mmol) and Pd(dppf)Cl ₂ (40 mg, 0.1 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 min and then stirred at 80° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (EtOAc in PE: 30% - 50%) to obtain 3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E7 , 300.0 mg) as a yellow gum. MS Calculated 731.4 (MH ⁺ ), Found 731.4 (MH ⁺ ).

Steps 7 ：Preparation (3 S )-1-[(2 S )-2-( Tertiary Butoxycarbonylamino )-3-[4-[6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1-(2,2,2- Trifluoroethyl ) Indole -5- base ] Thiazole -2- base ] Propionyl ] Hexahydro 𠯤 -3- Methyl formate (compound E8 ).

To a mixture of 3-[5-bromo-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound E7 , 0.3 g, 0.41 mmol) and (3 S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-(tributyloxycarbonylamino)propanoyl]hexahydrothiazol-3-carboxylic acid methyl ester (Intermediate B , 196.7 mg, 0.41 mmol) in toluene (3 mL), 1,4-dioxane (1 mL) and water (1 mL) was added K ₃ PO ₄ (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl ₂ (27.05 mg, 0.04 mmol). The mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (EtOAc in PE: 60% - 80%) to give ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydrotin-3-carboxylic acid methyl ester (Compound E8 , 200.0 mg) as a yellow gum. MS calcd. 1001.4 (MH ⁺ ), found 1001.4 (MH ⁺ ).

Steps 8 ：Preparation (3 S )-1-[(2 S )-2-( Tertiary Butoxycarbonylamino )-3-[4-[6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-1-(2,2,2- Trifluoroethyl ) Indole -5- base ] Thiazole -2- base ] Propionyl ] Hexahydro 𠯤 -3- Formic acid (compound E9 ).

To a mixture of ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydrothiazol-3-carboxylic acid methyl ester (Compound E8 , 200.0 mg, 0.2 mmol) in DCE (5 mL) was added _Me3SnOH (200.0 mg, 1.11 mmol). The mixture was stirred at 60°C for 12 hours. The reaction mixture was concentrated under vacuum to give a residue. To the residue was added EtOAc (10 mL) and water (10 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (15 mL, twice). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give (3 S )-1-[(2 S )-2-(tributyloxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydrotantalum-3-carboxylic acid (Compound E9 , 188.0 mg) as a brown solid. MS calcd. 987.4 (MH ⁺ ), found 987.4 (MH ⁺ ).

Steps 9 ：Preparation N -[(7 S ,13 S )-24- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Tributyl carbamate (compound E10 ).

To a mixture of ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridine-3-carboxylic acid (Compound E9 , 188.0 mg, 0.19 mmol) in DCM (20 mL) at 0°C were added DIEA (0.7 mL, 3.81 mmol), EDCI (550.0 mg, 2.87 mmol) and HOBt (65.0 mg, 0.48 mmol). After stirring at 20°C for 12 hours, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL), dried over _{Na2SO4 ,} filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography (EtOAc in PE: 50% - 70%) to give N -[( 7S , 13S )-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamic acid tributyl ester (Compound E10 , 110.0 mg). MS Calculated 969.4 (MH ⁺ ), Found 969.5 (MH ⁺ ).

Steps 10 ：Preparation (7 S ,13 S )-7- Amine -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-[4-(2,2,2- Trifluoroethyl ) Piperidone 𠯤 -1- base ]-3- Pyridyl ]-17,17- Dimethyl -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -8,14- Diketone (intermediate E ).

To N -[(7 S ,13 S )-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamic acid tributyl ester (Compound E10 , 110.0 mg, 0.11 mmol) in DCM To the solution in 4% paraformaldehyde (1 mL) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 20°C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a residue. Saturated aqueous NaHCO ₃ solution (20 mL) was added and the mixture was extracted with EtOAc (15 mL, three times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (7 S ,13 S) -7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]Octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate E , 98.0 mg). MS calculated value 869.4 (MH ⁺ ), found value 869.2 (MH ⁺ ).

Intermediate F

(7 S ,13 S )-7- amino -21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2- trifluoroethyl ) piperidin - 1- yl ]-3- pyridinyl ]-17,17- dimethyl -15- oxa - 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene -8,14 - dione

Analogously to the preparation of intermediate E , the title compound was prepared by using iodoethane instead of 2,2,2-trifluoroethyl triflate.

Intermediate G

(7 S ,13 S )-7- amino -21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ] -5-N- oxolinyl -3- pyridyl ]-17,17 - dimethyl -15 -oxa -4- thia -9,21,27,28 -tetraazapentacyclo- [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene -8,14- dione

Steps 1 ：Preparation 4-[5- bromine -6-[(1 S )-1- Methoxyethyl ]-3- Pyridyl ] Phenyline (compound G1 ）

To a mixture of 3-bromo-5-iodo-2-[( 1S )-1-methoxyethyl]pyridine (Compound A3 , 30 g, 87.73 mmol) and morpholine (7.6 g, 87.73 mmol) in toluene (450 mL) were added _Cs2CO3 ( _57.2 g, 175.45 mmol), ( R )-binap (2.7 g, 4.39 mmol) and Pd(OAc) ₂ (0.98 g, 4.39 mmol). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain 4-[5-bromo-6-[( 1S )-1-methoxyethyl]-3-pyridyl]morpholine (Compound G1 , 21 g) as a yellow oil. MS Calcd. 301.1 (MH ⁺ ), Found 301.1 (MH ⁺ ).

Steps 2 ：Preparation 4-[6-[(1 S )-1- Methoxyethyl ]-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-3- Pyridyl ] Phenyline (compound G2 ）

To a solution of 4-[5-bromo-6-[( 1S )-1-methoxyethyl]-3-pyridyl]morpholine (Compound G1 , 21 g, 63.3 mmol), bis(pinacol)borate (24.0 g, 94.63 mmol) and KOAc (13.6 g, 138.79 mmol) in toluene (500 mL) was added Pd(dppf) _Cl2 (4.4 g, 6.31 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90°C under nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product 4-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound G2 , 45 g) as a yellow gum, which was used in the next step. MS Calcd. 349.2 (MH ⁺ ), Found 349.2 (MH ⁺ ).

Steps 3 ：Preparation [3-[5- bromine -6- fluorine -2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-1 H - Indole -3- base ]-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound G3 ）

To a solution of 4-[6-[( 1S )-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]pyrroline (Compound G2 , 40.6 g, 46.65 mmol), [3-(5-bromo-6-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound C5 , 31 g, 46.65 mmol) in 1,4-dioxane (420 mL) and water (80 mL) _were added _K3PO4 (29.7 g, 2.33 mmol) and Pd(dppf) _Cl2 (1.7 g, 0.29 mmol). The mixture was degassed by bubbling nitrogen for 2 min, and the reaction mixture was stirred at 90°C for 18 h. After cooling to room temperature, the reaction mixture was extracted with EA (200 mL, three times). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain [3-[5-bromo-6-fluoro-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl] -1H -indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound G3 , 17.2 g) as a yellow oil. MS Calculated 758.3 (MH ⁺ ), Found 758.3 (MH ⁺ ).

Steps 4 ：Preparation [3-[5- bromine -1- Ethyl -6- fluorine -2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ] Indole -3- base ]-2,2- Dimethyl - Propoxy ]- Tertiary Butyl - Diphenyl - Silane (compound G4 ）

To a solution of [3-[5-bromo-6-fluoro-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl] -1H -indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound G3 , 15 g, 19.77 mmol) in DMF (300 mL) was added _Cs2CO3 ( _19.3 g, 59.3 mmol) and iodoethane (6.16 g, 39.53 mmol) at 0°C. After stirring at 20°C for 16 hours, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL, three times). The combined organic layers were washed with brine (10 mL, three times), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound G4 , 14.7 g) as a yellow oil. MS Calcd. 786.3 (MH ⁺ ), Found 786.4 (MH ⁺ ).

Steps 5 ：Preparation 3-[5- bromine -1- Ethyl -6- fluorine -(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ] Indole -3- base ]-2,2- Dimethyl - C -1- Alcohol (compound G5 )and 3-[5- bromine -1- Ethyl -6- fluorine -(2 P )-2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ] Indole -3- base ]-2,2- Dimethyl - C -1- Alcohol (compound G6 ）

To a solution of [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tributyl-diphenyl-silane (Compound G4 , 14.7 g, 18.68 mmol) in DMF (160 mL) was added cesium fluoride (14.2 g, 93.41 mmol). The mixture was stirred at 60°C for 48 hours. After cooling to room temperature, EtOAc (300 mL) and water (300 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, three times). The combined organic layers were washed with brine (200 mL, four times), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to give 3-[5-bromo-1-ethyl-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol as a colorless foam (Compound G5 , 6 g, faster elution) and 3-[5-bromo-1-ethyl-6-fluoro-(2 P )-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol as a colorless foam (Compound G6 , 4.5 g, slower elution). Compound G5 : MS calculated value 548.2 (MH ⁺ ), found value 548.2 (MH ⁺ ). ¹ H NMR (400MHz, methanol- d ₄ ) δ = 8.41 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.37 - 7.33 (m, 2H), 4.58 (s, 1H), 4.05 - 3.98 (m, 2H), 3.87-3.82 (m, 5H), 3.27 - 3.23 (m, 4H), 3.15 - 3.13 (m, 1H), 3.00 (s, 3H), 2.75-2.71 (m, 1H), 2.24 - 2.22 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H), 0.76 (s, 3H).

Compound G5 of X X-ray crystallography

The absolute structure of compound G5 was confirmed by single crystal X-ray crystallography (Figure 1).

Steps 6 ：Preparation 3-[1- Ethyl -6- fluorine -(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Indole -3- base ]-2,2- Dimethyl - C -1- Alcohol (compound G7 ）

To a solution of 3-[5-bromo-1-ethyl-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G5 , 6 g, 10.94 mmol), bis(pinacol)borate (4.2 g, 16.41 mmol) in toluene (60 mL) was added potassium acetate (2.7 g, 27.35 mmol) and Pd(dppf)Cl ₂ (0.8 g, 1.09 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 min and then stirred at 90° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain 3-[1-ethyl-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G7 , 4.5 g) as a colorless gum. MS calculated value 596.4 (MH ⁺ ), found value 596.4 (MH ⁺ ).

Steps 7 ：Preparation (3 S )-1-[(2 S )-2-( Tertiary Butoxycarbonylamino )-3-[4-[1- Ethyl -6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ] Indole -5- base ] Thiazole -2- base ] Propionyl ] Hexahydro 𠯤 -3- Methyl formate (compound G8 ）

To a mixture of 3-[1-ethyl-6-fluoro-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound G7 , 4.5 g, 7.56 mmol) and (3 S )-1-[(2 S )-3-(4-bromothiazol-2-yl)-2-(tributyloxycarbonylamino)propanoyl]hexahydropyridine-3-carboxylic acid methyl ester (Intermediate B , 3.6 g, 7.56 mmol) in toluene (45 mL), 1,4-dioxane (15 mL) and water (15 mL) was added K ₃ PO 4 ₄ (4.0 g, 18.89 mmol) and Pd(dtbpf)Cl ₂ (492.5 mg, 0.75 mmol). The mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydrothiazol-3-carboxylic acid methyl ester (Compound G8 , 3.8 g) as a colorless gum. MS Calculated 866.4 (MH ⁺ ), Found 866.4 (MH ⁺ ).

Steps 8 ：Preparation (3 S )-1-[(2 S )-2-( Tertiary Butoxycarbonylamino )-3-[4-[1- Ethyl -6- fluorine -3-(3- Hydroxyl -2,2- Dimethyl - Propyl )-(2 M )-2-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ] Indole -5- base ] Thiazole -2- base ] Propionyl ] Hexahydro 𠯤 -3- Formic acid (compound G9 ）

To a mixture of ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydrothiazol-3-carboxylic acid methyl ester (Compound G8 , 3.8 g, 4.39 mmol) in DCE (76 mL) was added _Me3SnOH (3.2 g, 17.55 mmol). The mixture was stirred at 60°C for 48 hours. The reaction mixture was concentrated under vacuum to give a residue. To the residue were added EtOAc (200 mL) and water (100 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL, twice). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give (3 S )-1-[(2 S )-2-(tributyloxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2 M )-2-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydrothiazol-3-carboxylic acid (Compound G9 , 3.7 g) as a brown solid. MS Calcd. 852.4 (MH ⁺ ), Found 852.4 (MH ⁺ ).

Steps 9 ：Preparation N -[(7 S ,13 S )-21- Ethyl -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Tributyl carbamate (compound G10 ）

To a mixture of ( 3S )-1-[( 2S )-2-(tributyloxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-( 2M )-2-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydrothiazol-3-carboxylic acid (Compound G9 , 2.5 g, 2.93 mmol) in DCM (250 mL) at 0°C were added DIEA (7.58 mL, 58.68 mmol), EDCI (8.4 g, 44.01 mmol) and HOBt (991.2 mg, 0.91 mmol). After stirring at 20 °C for 12 h, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography to give N -[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]Octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamic acid tributyl ester (Compound G10 , 1.2 g). MS calculated value 834.4 (MH ⁺ ), found value 834.4 (MH ⁺ ).

Steps 10 ：Preparation (7 S ,13 S )-7- Amine -twenty one- Ethyl -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-17,17- Dimethyl -15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -8,14- Diketone (intermediate G ）

To a solution of tributyl N -[( 7S , 13S )-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1( ²⁵ ),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound G10 , 1.2 g, 1.44 mmol) in DCM (12 mL) was added TFA (6.0 mL). The mixture was stirred at 20°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum to obtain a residue. Saturated aqueous NaHCO ₃ solution (60 mL) was added and the mixture was extracted with EtOAc (80 mL, three times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (7 S ,13 S )-7-amino-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate G) as a yellow solid. , 1 g). MS calcd. 734.3 (MH ⁺ ), found 734.3 (MH ⁺ ).

Intermediate H

(7 S ,13 S )-7- amino -25- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4- methylpiperidin - 1- yl )-3- pyridinyl ]-17,17- dimethyl -21-(2,2,2- trifluoroethyl )-15- oxa- 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene -8,14- dione

Analogously to the preparation of intermediate C , the title compound was prepared by using 5-bromo-4-fluoro- 1H -indole instead of 5-bromo-6-fluoro- 1H -indole (compound C2 ).

Intermediate I

(7 S ,13 S )-7- amino -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17 -dimethyl -21-(2,2,2- trifluoroethyl )-15- oxa- 4 -thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene- 8,14 - dione

Analogously to the preparation of intermediate E , the title compound was prepared by using morpholine instead of 1-(2,2,2-trifluoroethyl)piperidinium (Compound E1 ).

Intermediate J

(7 S ,13 S )-7- amino -25- fluoro- ( 20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin - 1- yl ]-3- pyridinyl ]-17,17- dimethyl -21-(2,2,2 -trifluoroethyl )-15- oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaene- 8,14- dione

Analogously to the preparation of intermediate E , the title compound was prepared by using [3-(5-bromo-4-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound J1 ) instead of [3-(5-bromo-6-fluoro-2-iodo- 1H -indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound C5 ).

Similar to the preparation of intermediate C5 , compound J1 was prepared by using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro- 1H -indole (compound C2 ).

Examples 1

3-( Dimethylamino ) -N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4- methylpiperidin -1- yl ) -3- pyridinyl ]-17,17 - dimethyl -8,14- dioxo -21-(2,2,2- trifluoroethyl )-15- oxa -4- thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -Methyl - tetrahydroacrylamide -1 - carboxamide

The compound was prepared according to the following scheme:

Steps 1 ：Preparation (2 S )-2-[ Tertiary Butoxycarbonyl ( methyl ) Amine ]-3- methyl - Benzyl butyrate (compound 1B ）

To a mixture of BOC- N -ME-VAL-OH (5.0 g, 21.62 mmol) and potassium carbonate (4.5 g, 32.43 mmol) in DMF (70 mL) at 0°C was added benzyl bromide (4.1 g, 23.78 mmol). The mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (200 mL), dried over _{Na2SO4 ,} filtered and concentrated in vacuo. The residue was purified by reverse phase column to obtain ( 2S )-2-[tributyloxycarbonyl(methyl)amino]-3-methyl-butyric acid benzyl ester (Compound 1B , 6.7 g) as a yellow oil. ^1H NMR (400 MHz, CHLOROFORM- d ) δ = 7.34 (br s, 5H), 5.21 - 5.10 (m, 2H), 2.88 - 2.74 (m, 3H), 2.31 - 2.12 (m, 1H), 1.68 - 1.64 (m, 1H), 1.44 (br d, J = 15.0 Hz, 9H), 0.96 (d, J = 6.6 Hz, 3H), 0.90 (br d, J = 3.8 Hz, 3H). MS calcd. 322.2 (MH ⁺ ), found 344.2 (MNa ⁺ ).

Steps 2 ：Preparation (2 S )-3- methyl -2-( Methylamino ) Benzyl butyrate (compound 1C ）

A mixture of ( 2S )-2-[tributyloxycarbonyl(methyl)amino]-3-methyl-butyric acid benzyl ester (Compound 1B , 6.7 g, 21.47 mmol) in HCl/1,4-dioxane (50.0 mL, 2 M) was stirred at 25°C for 1 h. After the reaction was completed, the reaction mixture was concentrated in vacuo to obtain a residue. The residue was diluted with saturated _NaHCO3 (40 mL) and extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (2 S )-3-methyl-2-(methylamino)butyric acid benzyl ester (Compound 1C , 4.7 g) as a colorless oil. MS Calcd. 222.1 (MH ⁺ ), Found 222.2 (MH ⁺ ).

Steps 3 ：Preparation (2 S )-2-[[3-( Dimethylamino ) Four Hydrogen -1- Carbonyl ]- methyl - Amine ]-3- methyl - Benzyl butyrate (compound 1D ）

To a mixture of ( 2S )-3-methyl-2-(methylamino)butyric acid benzyl ester (Compound 1C , 1.0 g, 4.52 mmol) and DIEA (0.9 mL, 4.97 mmol) in DCM (15 mL) at 0°C was added triphosgene (1.3 g, 4.52 mmol). After stirring for 0.5 h, a solution of N , N -dimethyltetrahydroazolidin-3-amine dihydrochloride (Compound 1D , 782.1 mg, 4.52 mmol) and DIEA (1.97 mL, 11.3 mmol) in DCM (4 mL) was added to the reaction. The reaction mixture was stirred at 20°C for another 1 h. After the reaction was complete, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL, twice). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give (2 S )-2-[[3-(dimethylamino)tetrahydroazine-1-carbonyl]-methyl-amino]-3-methyl-butyric acid benzyl ester (Compound 1E , 1.0 g) as a yellow oil. MS Calcd 348.2 (MH ⁺ ), Found 348.2 (MH ⁺ ).

Steps 4 ：Preparation (2 S )-2-[[3-( Dimethylamino ) Four Hydrogen -1- Carbonyl ]- methyl - Amine ]-3- methyl - Butyric acid (compound 1F ）

To a mixture of ( 2S )-2-[[3-(dimethylamino)tetrahydroazine-1-carbonyl]-methyl-amino]-3-methyl-butyric acid benzyl ester (Compound 1E , 500.0 mg, 1.44 mmol) in methanol (15 mL) was added Pd(OH) ₂ on activated carbon (400.0 mg, 0.57 mmol). The reaction mixture was degassed and purged with hydrogen three times and stirred at 20 °C under hydrogen atmosphere (15 psi) for 12 hours. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain ( 2S )-2-[[3-(dimethylamino)tetrahydroazine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (Compound 1F , 370.0 mg) as a yellow oil. MS calculated value 258.1 (MH ⁺ ), found value 258.3 (MH ⁺ ).

Steps 5 ：Preparation 3-( Dimethylamino )- N -[(1 S )-1-[[(7 S ,13 S )-24- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-(4- Methylpiperidone 𠯤 -1- base )-3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -21-(2,2,2- Trifluoroethyl )-15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Aminoformyl ]-2- methyl - Propyl ] -N- methyl - Four Hydrogen -1- Formamide (Example 1 ）

To a solution of ( 2S )-2-[[3-(dimethylamino)tetrahydroaziridine-1-carbonyl]-methyl-amino]-3-methyl-butanoic acid (Compound 1F , 32.13 mg, 0.12 mmol) in DMF (2 mL) at 0°C was added DIEA (0.1 mL, 0.25 mmol), HATU (47.47 mg, 0.12 mmol) and (7S,13S)-7-amino-24-fluoro-17,17-dimethyl-20-[5-(4-methylpiperidin-1-yl)-2-[rac-(1S)-1-methoxyethyl]-3-pyridinyl]-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C, 50.0 mg, 0.06 mmol). After stirring at 20°C for 1 h, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL, three times). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give Example 1 (35.1 mg) as a white solid. MS calcd 1040.5 (MH ⁺ ), found 1040.8 (MH ⁺ ), ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.68 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.57 - 7.44 (m, 2H), 5.79 - 5.69 (m, 1H), 5.25 - 5.11 (m, 1H), 4.97 - 4.89 (m, 2H), 4.51 - 4.39 (m, 2H), 4.31 - 4.12 (m, 7H), 4.12 - 3.88 (m, 2H), 3.87 - 3.67 (m, 3H), 3.67 - 3.52 (m, 2H), 3.47 (d, J = 14.8 Hz, 2H), 3.35 (s, 3H), 3.29 - 3.22 (m, 2H), 3.22 - 3.10 (m, 2H), 2.99 (s, 3H), 2.92 (s, 8H), 2.87 - 2.77 (m, 1H), 2.58 (d, J = 14.4 Hz, 1H), 2.30 - 2.16 (m, 2H), 2.03 - 1.90 (m, 1H), 1.88 - 1.74 (m, 1H), 1.72 - 1.58 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.03 - 0.89 (m, 9H), 0.45 (s, 3H).

Examples 2

3-( Dimethylamino ) -N -[(1 S )-1-[[(7 S ,13 S )-25- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4- methylpiperidin -1- yl ) -3- pyridinyl ]-17,17 - dimethyl -8,14- dioxo -21-(2,2,2- trifluoroethyl )-15- oxa -4- thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -Methyl - tetrahydroacrylamide -1 - carboxamide

The title compound was prepared similarly to Example 1 by using (7 S ,13 S )-7-amino-25-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (intermediate H ) instead of (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25 ) ,2,5(28),19,22(26),23-hexene-8,14-dione (intermediate H ) M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ). Example 2 (50.0 mg) was obtained as a yellow solid. MS calculated 1040.5 (MH ⁺ ), found 1040.8 (MH ⁺ ). ¹ H NMR (400MHz, methanol- d ₄ ) δ = 8.55 - 8.49 (m, 1H), 7.63 - 7.56 (m, 1H), 7.52 - 7.39 (m, 3H), 6.03 - 5.81 (m, 1H), 5.20 - 5.01 (m, 1H), 4.70 - 4.61 (m, 1H), 4.45 - 4.36 (m, 2H), 4.30 - 4.23 (m, 2H), 4.17 - 3.93 (m, 7H), 3.77 - 3.63 (m, 3H), 3.56 - 3.48 (m, 2H), 3.42 - 3.34 (m, 2H), 3.29 - 3.21 3H), 3.20 - 3.11 (m, 3H), 3.00 - 2.98 (m, 3H), 2.94 - 2.87 (m, 10H), 2.68 - 2.51 (m, 2H), 2.23 - 2.14 (m, 1H), 1.68 - 1.53 (m, 1H), 1.47 - 1.41 (m, 3H), 1.35 - 1.15 (m, 3H), 0.95 - 0.88 (m, 6H), 0.81 (s, 3H), 0.72 - 0.58 (m, 3H).

Examples 3

N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4 -methylpiperidin - 1- yl )-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4-thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28), 19,22 (26),23- hexaen -7- yl ] aminocarbonyl ]-2 - methyl - propyl ]- N -methyl - oxoline - 4 -carboxamide

The title compound was prepared similarly to the preparation of Example 1 by using morpholine instead of N , N -dimethyltetrahydroazolidin-3-amine dihydrochloride (Compound 1D ). Example 3 (25 mg) was obtained as an off-white solid. MS calcd 1027.4 (MH ⁺ ), found 1027.7 (MH ⁺ ), ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.71 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 2.8 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.48 (d, J = 12.8 Hz, 1H), 5.76 (d, J = 8.8 Hz, 1H), 5.26 - 5.13 (m, 1H), 4.84 - 4.75 (m, 1H), 4.43 (d, J = 12 Hz, 1H), 4.30 - 4.24 (m, 1H), 4.26 (dd, J = 12, 2.8 Hz, 1H), 4.17 - 4.03 (m, 2H), 4.00 (s, 1H), 3.85 - 3.62 (m, 8H), 3.55 - 3.44 (m, 2H), 3.42 - 3.34 (m, 6H), 3.30 - 3.18 (m, 5H), 3.15 - 3.09 (m, 1H), 2.99 (s, 3H), 2.91 (s, 3H), 2.87 - 2.77 (m, 1H), 2.71 - 2.58 (m, 1H), 2.33 - 2.14 (m, 2H), 2.01 - 1.90 (m, 1H), 1.87 - 1.74 (m, 1H), 170 - 1.57 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.01 - 0.87 (m, 9H), 0.50 (s, 3H).

Examples 4

3-( Dimethylamino ) -N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- pyridinyl -3- pyridyl ]-17,17 -dimethyl -8,14- dioxo- 21-(2,2,2- trifluoroethyl )-15- oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -Methyl - tetrahydroacrylamide -1 - carboxamide

The title compound was prepared similarly to Example 1 by using (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (Intermediate I ) instead of (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ). Example 4 (12.9 mg) was obtained as a yellow solid. MS Calcd. 1027.5 (MH ⁺ ), Found. 1027.5 (MH ⁺ ). ¹ H NMR (400MHz, methanol- d ₄ ) δ = 8.69 (d, J = 7.8 Hz, 1H), 8.42 (d, J = 2.9 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 12.7 Hz, 1H), 5.74 (br d, J = 9.3 Hz, 1H), 5.18 (br dd, J = 8.3, 16.6 Hz, 1H), 4.87 - 4.79 (m, 2H), 4.49 - 4.38 (m, 2H), 4.33 - 4.11 (m, 7H), 3.87 (t, J = 4.6 Hz, 4H), 3.78 (br d, J = 11.2 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.48 (br d, J = 14.7 Hz, 1H), 3.39 - 3.33 (m, 6H), 3.26 - 3.21 (m, 1H), 3.15 - 3.10 (m, 1H), 2.97 - 2.90 (m, 8H), 2.89 - 2.76 (m, 2H), 2.66 - 2.60 (m, 1H), 2.26 - 2.17 (m, 2H), 2.01 - 1.91 (m, 1H), 1.87 - 1.78 (m, 1H), 1.70 - 1.60 (m, 9H), 0.48 (s, 3H).

Examples 5

N -[(1 S )-1-[[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- morpholinyl -3- pyridyl ]-17,17 -dimethyl -8,14- dioxo- 15 - oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2- methyl - propyl ]- N -methyl- morpholinyl - 4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[ ^{17.5.2.12,5.19,13.022,26} ] ^octacosyl -1(25),2,5(28),19,22(26),23-hexene-8,14-dione (Intermediate G ) instead of N , N -dimethyltetrahydroazolidin-3-amine dihydrochloride (Compound 1D) ^. ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1( ²⁵ ),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ). Example 5 (131.3 mg) was obtained as a yellow solid. MS calcd. 960.5 (MH ⁺ ), found 960.3 (MH ⁺ ). ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.97 (br d, J = 1.6 Hz, 1H), 8.69 (d, J = 7.5 Hz, 1H), 8.14 - 7.98 (m, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 12.5 Hz, 1H), 5.81 (br d, J = 17.7 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.41 (d, J = 6.5 Hz, 1H), 4.29 - 4.22 (m, 1H), 4.19 - 4.28 (m, 2H), 3.84 - 3.78 (m, 2H), 3.77 - 3.70 (m, 3H), 3.49 - 3.42 (m, 6H), 3.39 - 3.31 (m, 6H), 3.23 - 3.14 (m, 2H), 2.91 (s, 3H), 2.77 - 2.68 (m, 1H), 2.49 - 2.42 (m, 1H), 2.38 - 2.28 (m, 2H), 2.02 - 1.96 (m, 2H), 1.82 (br d, J = 12.7 Hz, 1H), 1.69 - 1.60 (m, 1H), 1.57 (d, J = 6.2 Hz, 3H), 1.03 - 0.96 (m, 9H), 0.91 (d, J = 6.6 Hz, 3H), 0.55 - 0.43 (m, 3H).

Examples 6

N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin -1- yl ]-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4 - thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -Methyl - morpholine -4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25), ^2,5 (28),19,22( ²⁶ ),23-hexaene-8,14-dione (Intermediate E ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1 D ) and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) were used to prepare the product. Example 6 (8.8 mg) was obtained as an off-white solid. MS calcd. 1095.5 (MH ⁺ ), found 1095.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.71 (d, J = 7.2 Hz, 1H), 8.45 - 8.38 (m, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.48 (d, J = 12.8 Hz, 1H), 5.87 - 5.69 (m, 1H), 5.24 - 5.11 (m, 1H), 4.49 - 4.37 (m, 1H), 4.29 - 4.16 (m, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.83 - 3.57 (m, 7H), 3.50 - 3.36 (m, 7 - 1.54 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.34 - 1.26 (m, 1H), 1.00 - 0.88 (m, 9H), 0.50 (s, 3H).

Examples 7

N -[(1 S )-1-[[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17 -dimethyl -8,14- dioxo- 15 - oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl- 1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2 - methyl - propyl ]-3,3 -difluoro- N -methyl - tetrahydroazol - 1 - carboxamide

The compound was prepared according to the following scheme:

Steps 1 : N -[(1 S )-1-[[(7 S ,13 S )-21- Ethyl -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Aminoformyl ]-2- methyl - Propyl ] -N- methyl - Tributyl carbamate (compound 7A ）

To a solution of BOC- N -ME-VAL-OH (Compound 1A , 66.2 mg, 0.29 mmol) in DMF (1 mL) at 0°C were added DIEA (0.3 mL, 1.90 mmol) and HATU (67.3 mg, 0.29 mmol). After stirring at 0°C for 15 min, the reaction mixture was added with ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[ ^{17.5.2.12,5.19,13.022,26 ]} octacosyl-1(25),2,5(28),19,22(26) ^, 23-hexaene-8,14-dione (Intermediate G , 70.0 mg, 0.09 mmol). After stirring the reaction at 20°C for 0.5 h, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL, three times). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative TLC to give N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 -Methyl-carbamic acid tributyl ester (Compound 7A , 65.1 mg). MS calculated value 947.5 (MH ⁺ ), found value 947.4 (MH ⁺ ).

Steps 2 : [(1 S )-1-[[(7 S ,13 S )-21- Ethyl -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Aminoformyl ]-2- methyl - Propyl ]- methyl - ammonium; 2,2,2- Trifluoroacetate (Compound 7B ）

At 20°C, N -[(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-fluorinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl] -N -methyl-carbamic acid tributyl ester (Compound 7A , 40.0 mg, 0.04 To a mixture of 4-(4-(2 ... The residue was purified by preparative HPLC to give [(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-methyl-ammonium; 2,2,2-trifluoroacetate (Compound 7B , 20.0 mg). MS calculated value 847.5 (MH ⁺ ), found value 847.4 (MH ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.68 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.56 (br s, 1H), 7.35 (d, J = 12.6 Hz, 1H), 5.95 - 5.92 (m, 1H), 5.04 - 4.96 (m, 1H), 4.94 - 4.91 (m, 3H), 4.45 - 4.40 (m, 1H), 4.35 - 4.07 (m, 4H), 3.88 - 3.83 (m, 4H), 3.80 - 3.69 (m, 3H), 3.56 - 3.50 (d, J = 14.5 Hz, 1H), 3.35 - 3.31 (m, 4H), 3.07 - 2.97 (m, 1H), 2.90 - 2.80 (m, 1H), 2.75 - 2.65 (m, 4H), 2.30 - 2.15 (m, 2H), 2.03 - 1.91 (m, 1H),1.89 - 1.75 (m, 1H), 1.73 - 1.56 (m, 1H), 1.45 - 1.43 (m, 3H), 1.15 - 1.09 (m, 3H), 1.09 - 1.07 (m, 3H), 1.03 - 1.01 (m, 3H), 0.95 (s, 3H), 0.56 (s, 3H).

Steps 3 : N -[(1 S )-1-[[(7 S ,13 S )-21- Ethyl -twenty four- fluorine -(20 M )-20-[2-[(1 S )-1- Methoxyethyl ]-5-N- Morpholinyl -3- Pyridyl ]-17,17- Dimethyl -8,14- Dioxygen -15- Oxygen impurities -4- Sulfur impurities -9,21,27,28- Tetrazolyl Pentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] Twenty-eight base -1(25),2,5(28),19,22(26),23- Hexaene -7- base ] Aminoformyl ]-2- methyl - Propyl ]-3,3- Difluoro -N- methyl - Four Hydrogen -1- Formamide （ Examples 7 ）

At 0°C, [(1 S )-1-[[(7 S ,13 S )-21-ethyl-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-fluorinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-methyl-ammonium; 2,2,2-trifluoroacetate (Compound 7B , 50.0 mg, 0.06 To a solution of 4- _nitropropene ( 7 _{- nitropropene} ... The residue was purified by preparative HPLC to give Example 7 (13.0 mg) as a light yellow solid. MS calcd. 966.5 (MH ⁺ ), found 966.4 (MH ⁺ ). ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.70 - 8.64 (m, 1H), 8.49 - 8.35 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 12.8 Hz, 1H), 5.78 (br t, J = 8.2 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.68 - 4.52 (m, 1H), 4.46 - 4.43 (m, 1H), 4.42 - 4.32 (m, 4H), 4.22 - 4.05 (m, 3H), 3.93 - 3.82 (m, 9 (m, 4H), 3.81 - 3.66 (m, 2H), 3.50 - 3.42 (m, 1H), 3.35 - 3.31 (m, 6H), 3.28 - 3.21 (m, 1H), 3.09 - 2.96 (m, 1H), 2.88 (s, 3H), 2.84 - 2.77 (m, 1H), 2.26 - 2.14 (m, 2H), 1.95 - 1.90 (m, 1H), 1.87 - 1.74 (m, 1H), 1.69 - 1.59 (m, 1H), 1.43 (d, J = 6.2 Hz, 3H), 1.36 - 1.27 (m, 2H), 1.03 - 0.89 (m, 12H), 0.53 (s, 3H).

Examples 8

(2 S )- N -[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17- dimethyl -8,14- dioxo - 15 -oxo- 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen- 7 -yl ]-3- methyl -2-(3- methyl -2- oxo - imidazolidin -1- yl ) butyramide

The title compound was prepared similarly to Example 1 by using ( 2S )-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butanoic acid (Compound 8H ) and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23 ^- hexene-8,14 ^- dione (Intermediate G ) replaced (2 S )-2-[[3-(dimethylamino)tetrahydroazine-1-carbonyl]-methyl-amino]-3-methyl-butyric acid (Compound 1F ) and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate C ). Example 8 (50.4 mg) was obtained as a yellow solid. MS calculated value 916.5 (MH ⁺ ), found value 916.3 (MH ⁺ ). ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.84 (br s, 1H), 8.66 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 12.3 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 5.83 (t, J = 9.0 Hz, 1H), 4.59 (br d, J = 11.9 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.27 - 4.14 (m, 2H), 4.11 - 4.03 (m, 1H), 3.95 (s, 1H), 3.93 - 3.89 (m, 4H), 3.84 (br d, J = 11.5 Hz, 1H), 3.71 (d, J = 11.0 Hz, 1H), 3.52 - 3.46 (m, 1H), 3.42 - 3.31 (m, 11H), 3.21 - 3.07 (m, 3H), 2.89 (s, 3H), 2.76 - 2.59 (m, 2H), 2.46 (br d, J = 14.4 Hz, 1H), 2.29 - 2.18 (m, 2H), 2.00 - 1.91 (m, 1H), 1.80 (br d, J = 12.2 Hz, 1H), 1.66 - 1.59 (m, 1H), 1.54 - 1.50 (m, 3H), 1.00 - 0.90 (m, 12H), 0.49 (s, 3H).

Compound 8H was prepared according to the following scheme:

Steps 1 ：Preparation (2 S )-2-( Tertiary Butoxycarbonylamino )-3- methyl - Benzyl butyrate (compound 8B ）

To a mixture of BOC-L-valine (Compound 8A , 1.0 g, 4.6 mmol) and potassium carbonate (763.4 mg, 5.52 mmol) in DMF (10 mL) at 0°C was added benzyl bromide (0.6 mL, 5.06 mmol). The mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (70 mL, three times). The combined organic layers were washed with brine (50 mL), dried over _{Na2SO4 ,} filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain ( 2S )-2-(tert-butyloxycarbonylamino)-3-methyl-butyric acid benzyl ester (Compound 8B , 1.0 g) as a colorless oil. MS Calcd. 307.4 (MH ⁺ ), Found 208.0 (M-Boc+H ⁺ ).

Steps 2 ：Preparation (2 S )-2- Amine -3- methyl - Benzyl butyrate (compound 8C ）

To a mixture of ( 2S )-2-(tributyloxycarbonylamino)-3-methyl-butyric acid benzyl ester (Compound 8B , 1.0 g, 3.11 mmol) in THF (5 mL) at 0°C was added HCl/dioxane (20.0 mL, 80.0 mmol, 4 N). After the reaction was stirred at 25°C for 1 h, the reaction mixture was concentrated under vacuum to give a yellow gum. The gum was diluted with aqueous _NaHCO3 (40 mL) and extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give (2 S )-2-amino-3-methyl-butyric acid benzyl ester (Compound 8C , 600.0 mg) as a colorless oil, which was used in the next step without purification.

Steps 3 ：Preparation (2 S )-2-[2-[ Tertiary Butoxycarbonyl ( methyl ) Amine ]- Ethylamino ]-3- methyl - Benzyl butyrate (compound 8E ）

To a solution of ( 2S )-2-amino-3-methyl-butyric acid benzyl ester (Compound 8C , 600.0 mg, 2.89 mmol) and N -BOC-(methylamino)acetaldehyde (Compound 8D , 601.7 mg, 3.47 mmol) in methanol (20 mL) was added _MgSO4 (2.1 g, 14.47 mmol). After stirring at 20°C for 1 h, NaBH(OAc) ₃ (1.2 g, 5.79 mmol) was added to the reaction mixture, and stirred at 20°C for another 1 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain a colorless oil. The oil was purified by column chromatography to obtain ( 2S )-2-[2-[tert-butyloxycarbonyl(methyl)amino]-ethylamino]-3-methyl-butyric acid benzyl ester (Compound 8E , 700.0 mg) as a colorless gum. MS Calcd. 365.2 (MH ⁺ ), Found 365.1 (MH ⁺ ).

Steps 4 ：Preparation (2 S )-3- methyl -2-[2-( Methylamino ) Ethylamino ] Benzyl butyrate; hydrochloride (compound 8F ）

To a solution of ( 2S )-2-[2-[tributyloxycarbonyl(methyl)amino]-ethylamino]-3-methyl-butyric acid benzyl ester (Compound 8E , 700.0 mg, 1.92 mmol) in THF (5 mL) at 0°C was added HCl/dioxane (15.0 mL, 60.0 mmol, 4 N). After stirring at 25°C for 2 hours, the reaction mixture was concentrated under vacuum to give a white solid. The residual solvent was removed by azeotropic distillation with THF twice to give ( 2S )-3-methyl-2-[2-(methylamino)ethylamino]butyric acid benzyl ester; hydrochloride (Compound 8F , 600.0 mg) as a white solid. It was used directly in the next step without further purification. Calculated: 265.2 (MH ⁺ ), Found: 265.2 (MH ⁺ ).

Steps 5 ：Preparation (2 S )-3- methyl -2-(3- methyl -2- Lateral oxygen - Imidazolidine -1- base ) Benzyl butyrate (compound 8G ）

To a solution of ( 2S )-3-methyl-2-[2-(methylamino)ethylamino]butyric acid benzyl ester; hydrochloride (Compound 8F , 600.0 mg, 1.99 mmol) and DIEA (772.5 mg, 5.98 mmol) in ACN (50 mL) was added CDI (646.4 mg, 3.99 mmol). After stirring at 0°C for 2 hours, water (10 mL) was added _to the reaction mixture, and extracted with EA (40 mL, twice). The combined organic layers were washed with brine (20 mL), dried ( _Na2SO4 ), and concentrated under vacuum to give a yellow gum. The gum was purified by reverse phase column to obtain ( 2S )-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butyric acid benzyl ester (Compound 8G , 300.0 mg) as a colorless gum. MS Calculated 291.2 (MH ⁺ ), Found 291.2 (MH ⁺ ).

Steps 6 ：Preparation (2 S )-3- methyl -2-(3- methyl -2- Lateral oxygen - Imidazolidine -1- base ) Butyric acid (compound 8H ）

To a solution of ( 2S )-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butyric acid benzyl ester (Compound 8G , 280.0 mg, 0.96 mmol) in methanol (10 mL) was added Pd(OH) ₂ on activated carbon (0.2 g, 10% purity). The reaction mixture was hydrogenated at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give ( 2S )-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butyric acid (Compound 8H , 150.0 mg) as a colorless gum. MS Calcd. 201.1 (MH ⁺ ), Found 201.0 (MH ⁺ ).

Examples 9

N -[(1 S )-1-[[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[ 4- (2,2,2- trifluoroethyl ) piperidin - 1- yl ]-3- pyridinyl ]-17,17 - dimethyl -8,14 - dioxo- 15 - oxa-4-thia- 9,21,27,28- tetraazapentacyclo [ 17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2- methyl - propyl ]- N -methyl- oxoline - 4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia- ^9,21,27,28 - ^{tetraazapentacyclo} [17.5.2.12,5.19,13.022,26]octacosyl-1(25),2,5(28),19,22(26), ²³ -hexaene-8,14-dione (Intermediate F ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 9 (26.8 mg) was obtained as an off-white solid. MS calcd. 1041.5 (MH ⁺ ), found 1041.7 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.71 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 12.8 Hz, 1H), 5.86 (d, J = 8.4 Hz, 1H), 4.48 - 4.32 (m, 2H), 4.30 - 4.19 (m, 1H), 4.18 - 4.11 (m, 1H), 4.08 - 3.97 (m, 2H), 3.80 - 3.67 (m, 6H), 3.51 - 3.47 (m, 4H), 3.39 - 3.33 (m, 5H), 3.29 - 3.08 (m, 6H), 3.03 - 2.96 (m, 1H), 2.93 - 2.84 (m, 7H), 2.84 - 2.70 (m, 2H), 2.28 - 2.14 (m, 2H), 1.99 - 1.92 (m, 1H), 1.86 - 1.74 (m, 1H), 1.70 - 1.58 (m, 1H), 1.48 - 1.43 (d, J = 6.0 Hz, 3H) 1.03 (t, J = 6.8 Hz, 3H), 0.96 - 0.89 (m, 9H), 0.61 (s, 3H).

Examples 10

N -[(1 S )-1-[[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-(4 -methylpiperidin - 1 - yl )-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -15 - oxa-4- thia - 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2- methyl - propyl ]- N -methyl- oxoline - 4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-15-oxa-4- ^thia - ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (Intermediate D ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 10 (10.3 mg) was obtained as a yellow solid. MS calcd. 973.5 (MH ⁺ ), found 973.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.67 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 2.8 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.34 (d, J = 12.4 Hz, 1H), 5.80 (d, J = 8.8 Hz, 1H), 4.43 (d, J = 10.8 Hz, 1H), 4.36 - 4.28 (m, 1H), 4.27 - 4.05 (m, 4H), 4.01 (d, J = 10.8 Hz, 1H), 3.81 - 3.62 (m, 8H), 3.49 - 3.43 (m, 2H), 3.42 - 3.33 (m, 7H), 3.29 - 3.17 (m, 4H), 3.07 - 3.02 (m, 1H), 2.99 (s, 3H), 2.89 (s, 3H), 2.86 - 2.79 (m, 1H), 2.67 - 2.63 (m, 1H), 2.30 - 2.15 (m, 2H), 2.01 - 1.91 (m, 1H), 1.86 - 1.74 (m, 1H), 1.70 - 1.57 m, 1H), 1.44 (d, J = 6.0 Hz, 3H), 1.03 - 0.88 (m, 13H), 0.53 (s, 3H).

Examples 11

N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro -20-(20 M )-[2-[(1 S )-1- methoxyethyl ]-5-N- morpholinyl -3- pyridyl ]-17,17 - dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa-4- thia - 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2- methyl - propyl ]- N -methyl- morpholinyl - 4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26), ²³ -hexene-8,14-dione (Intermediate I ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 11 (26.3 mg) was obtained as a white solid. MS calcd. 1013.5 (MH ⁺ ), found 1013.8 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.71 (d, J = 7.6 Hz, 1H), 8.49 - 8.35 (d, J = 2.8, 1H), 7.73 - 7.69 (d, J = 2.4, 1H), 7.66 - 7.59 (d, J = 2.4, 1H), 7.53 - 7.43 (d, J = 12.4, 1H), 5.88 - 5.70 (d, J = 8.8, 1H), 5.25 - 5.13 (m, 1H), 4.53 - 4.38 (m, 1H), 4.31 - 4.15 (m, 2H), 4.07 - 3.98 (d, J = 10.8, 1H), 91 - 3.84 (t, J = 4.8, 4H), 3.83 - 3.67 (m, 6H), 3.52 - 3.45 (m, 1H), 3.43 - 3.34 (m, 10H), 3.30 - 3.18 (m, 3H), 3.11 (m, 1H), 2.99 - 2.89 (s, 3H), 2.88 - 2.78 (m, 1H), 2.72 - 2.60 (d, J = 14.8, 1H), 2.34 - 2.15 (m, 2H), 2.01 - 1.91 (m, 1H), 1.90 - 1.74 (m, 1H), 1.72 - 1.57 (m, 1H), 1.52 - 1.42 (d, J = 6.0, 3H), 1.05 - 0.88 (m, 9H), 0.57 - 0.45 (s, 3H).

Examples 12

3-( Dimethylamino ) -N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin - 1- yl ]-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa -4- thia -9,21,27,28 -tetraazapentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2 -methyl - propyl ] -N - methyl - tetrahydroazol -1 -carboxamide

The title compound was prepared similarly to Example 1 by using (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (Intermediate E ) instead of (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ). Example 12 (45.3 mg) was obtained as a white solid. MS calcd. 1108.5 (MH ⁺ ), found 1108.5 (MH ⁺ ). ¹ H NMR (400MHz, methanol- d ₄ ) δ = 8.68 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 12.8 Hz, 1H), 7.32 -7.27 (m, 1H), 5.74 - 5.68 (m, 1H), 5.18 - 5.06 (m, 2H), 4.93 - 5.00 (m, 2H), 4.58 - 4.56(m, 5H), 4.32 - 4.23 (m, 1H), 4.22 - 4.14 (m, 2H), 4.14 - 4.07 (m, 1H), 7 - 3.5 (m, 1H), 4.00 - 3.89 (m, 1H), 3.87 - 3.67 (m, 2H), 3.53 - 3.39 (m, 1H), 3.34 - 3.32 (m, 4H), 3.19 - 3.09 (m, 4H), 2.90 - 2.79 (m, 8H), 2.63 - 2.54 (m, 1H), 2.26 - 2.15 (m, 8H), 1.57 - 1.98 (m, 3H), 1.43 (d, J = 6.0 Hz, 3H), 0.99 - 0.89 (m, 9H), 0.44 (s, 3H).

Examples 13

(2 S )- N -[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17 - dimethyl -8,14- dioxo- 15 -oxa - 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen- 7- yl ]-3- methyl -2-[ methyl (2,2,2- trifluoroethylaminomethyl ) amino ] butyramide

The title compound was prepared similarly to Example 1 by using 2,2,2-trifluoroethylamine and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26), ^{23 -} hexene-8,14-dione (Intermediate G ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 13 (13.4 mg) was obtained as a white solid. MS calcd. 972.4 (MH ⁺ ), found 972.4 (MH ⁺ ). ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.64 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.10 (s, 1H), 7.08 - 7.03 (m, 2H), 5.84 (t, J = 9.1 Hz, 1H), 5.21 (br s, 1H), 4.58 (br d, J = 12.1 Hz, 1H), 4.32 - 4.21 (m, 3H), 4.08 - 4.02 (m, 2H), 3.92 - 3.88 (m, 4H), 3.84 (br d, J = 11.0 Hz, 3H), 3.73 - 3.70 (m, 1H), 3.38 (s, 3H), 3.27 - 3.21 (m, 4H), 3.17 - 3.04 (m, 2H), 2.97 (s, 3H), 2.74 - 2.65 (m, 1H), 2.46 (br d, J = 14.4 Hz, 1H), 2.31 - 2.21 (m, 5H), 1.96 (br d, J = 13.7 Hz, 1H), 1.85 - 1.72 (m, 1H), 1.66 - 1.54 (m, 1H), 1.44 (d, J = 6.1 Hz, 3H), 1.25 (t, J = 7.0 Hz, 1H), 0.99 - 0.86 (m, 12H), 0.45 (s, 3H).

Examples 14

N -[(1 S )-1-[[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17 -dimethyl -8,14- dioxo- 15 - oxa- 4 - thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl- 1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminocarbonyl ]-2- methyl - propyl ]- N -methyl - 3-( trifluoromethyl ) tetrahydroazol- 1- carboxamide

The title compound was prepared similarly to Example 1 by using 3-(trifluoromethyl)tetrahydroaziridine and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl- ¹ (25),2,5( ²⁸ ),19,22(26),23-hexene-8,14-dione (Intermediate G ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 14 (3.1 mg) was obtained as a white solid. MS calcd. 998.5 (MH ⁺ ), found 998.5 (MH ⁺ ). ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.64 (d, J = 7.5 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.58 (s, 1H), 7.32 (br d, J = 9.6 Hz, 1H), 7.11 - 7.04 (m, 2H), 5.81 (br t, J = 8.8 Hz, 1H), 4.59 (br d, J = 9.8 Hz, 1H), 4.35 (br t, J = 8.7 Hz, 1H), 4.30 - 4.21 (m, 4H), 4.13 (br dd, J = 7.9, 15.0 Hz, 3H), 4.08 - 3.99 (m, 2H). 3H), 3.90 (br s, 4H), 3.84 (br d, J = 11.3 Hz, 1H), 3.43 (br d, J = 14.6 Hz, 1H), 3.37 (s, 3H), 3.24 (br d, J = 4.3 Hz, 4H), 3.18 - 3.13 (m, 1H), 2.84 (s, 3H), 2.75 - 2.62 (m, 1H), 2.47 (br d, J = 14.4 Hz, 1H), 2.31 - 2.17 (m, 2H), 2.05 (s, 3H), 1.94 (br d, J = 1.8 Hz, 1H), 1.51 (br s, 2H), 1.46 - 1.46 (m, 1H), 1.44 - 1.44 (m, 1H), 1.15 (td, J = 6.4, 13.0 Hz, 12H), 0.46 (s, 3H).

Examples 15

(2 S )- N -[(7 S ,13 S )-21- ethyl -24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N- oxolinyl -3- pyridyl ]-17,17- dimethyl -8,14- dioxo - 15 -oxo- 4 -thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ]-3- methyl -2-(3- oxo -5,6,8,8a- tetrahydro -1 H -imidazo [5,1-c][ 1,4 ] oxazolidinone -2- yl ) butyramide

Similarly to the preparation of Example 1 , the title compound was prepared by using (2S)-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidin-2-yl)butanoic acid (Compound 15g ) and ( 7S , 13S )-7-amino-21-ethyl-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1 ^{2,5.1 9,13.0 22,26} ] octadecyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (intermediate G ) replaced (2 S )-2-[[3-(dimethylamino)tetrahydroazir-1-carbonyl]-methyl-amino]-3-methyl-butyric acid (Compound 1F ) and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic [17.5.2.1 ^2,5 .1 ^{9,13.0 22,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate C ). Example 15 (37.5 mg) was obtained as a white solid. MS calculated value 958.5 (MH ⁺ ), found value 958.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.70 - 8.61 (m, 1H), 8.53 - 8.30 (m, 1H), 7.64 - 7.59 (m, 1H), 7.38 - 7.27 (m, 2H), 5.86 - 5.72 (m, 1H), 5.03 - 4.92 (m, 1H), 4.82 - 4.78 (m, 1H), 4.67 - 4.53 (m, 3H), 4.47 - 4.36 (d, J =12.8 Hz,1H), 4.29 - 4.12 (m, 4H), 4.10 - 4.01 (d, J =10.8 Hz,1H), 3.89 - 3.84 9 - 2.87 (m, 1H), 1.70 - 1.89 (m, 1H), 1.77 - 1.86 (m, 1H), 1.62 - 1.54 (m, 1H), 1.51 - 1.37 (m, 3H), 1.08 - 2.71 (m, 4H), 1.10 - 2.87 (m, 4H), 1.11 - 2.91 (m, 2H), 1.09 - 2.83 (m, 1H), 1.12 - 2.84 (m, 3H), 1.22 - 1.42 (m, 4H), 1.22 - 1.70 (m, 3H), 1.08 - 2.81 (m, 1H), 1.14 - 2.83 (m, 3H), 1.20 - 2.81 (m, 1H), 1.24 - 2.19 (m, 2H), 1. 12H), 0.62 - 0.42 (m, 3H).

Compound 15g was prepared according to the following procedure:

Steps 1 : 3-[[(1 S )-1- Benzyloxycarbonyl -2- methyl - Propyl ] Aminoformyl ]- Morpholine -4- Tributyl formate (compound 15c ）

To a solution of 4-tert-butyloxycarbonylmorpholine-3-carboxylic acid (compound 15b , 2.8 g, 12.31 mmol) and L-valeric acid benzyl ester hydrochloride (compound 15a , 3.0 g, 12.31 mmol) in DMF (30 mL) were added DIEA (4.29 mL, 24.62 mmol) and HATU (5.1 g, 13.54 mmol). After stirring at 25 °C for 1 h, EtOAc (40 mL) and water (40 mL) were added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to give tert-butyl 3-[[(1 S )-1-benzyloxycarbonyl-2-methyl-propyl]aminoformyl]morpholine-4-carboxylate (Compound 15c , 7.5 g) as a white oil. MS Calcd. 420.23 (MH ⁺ ), Found 321.2 (M-Boc+H ⁺ ).

Steps 2 : (2 S )-3- methyl -2-( Morpholine -3- Carbonylamino )- Benzyl butyrate; hydrochloride (compound 15d ）

To a solution of 3-[[( 1S )-1-benzyloxycarbonyl-2-methyl-propyl]aminomethyl]-pyroline-4-carboxylic acid tributyl ester (Compound 15c , 7.2 g, 17.16 mmol) in 1,4-dioxane (10 mL) was added 1,4-dioxane/HCl (4 M, 15.0 mL, 60.0 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give ( 2S )-3-methyl-2-(pyroline-3-carbonylamino)-butyric acid benzyl ester; hydrochloride (Compound 15d , 6.7 g) as a white oil. MS Calcd. 321.2 (MH ⁺ ), Found 321.2 (MH ⁺ ).

Steps 3 : (2 S )-2-(1,3- Dioxygen -5,6,8,8a- Tetrahydroimidazole [5,1-c][1,4] 㗁 𠯤 -2- base )-3- methyl - Benzyl butyrate (compound 15e ）

To a solution of (2S)-3-methyl-2-(morpholine-3-carbonylamino)-butyric acid benzyl ester (compound 15d , 6.5 g, 20.29 mmol) in THF (1 mL) was added TEA (8.5 mL, 60.87 mmol) and N.N' -carbonyldiimidazole (3.9 g, 24.35 mmol). After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by reverse phase chromatography to give ( 2S )-2-(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[5,1-c][1,4]oxazolidin-2-yl)-3-methyl-butyric acid benzyl ester (Compound 15e , 2.36 g) as a white oil. MS Calcd. 346.4 (MH ⁺ ), Found 369.4 (MNa ⁺ ).

Steps 4 : (2 S )-3- methyl -2-(1- Lateral oxygen -5,6,8,8a- Tetrahydrogen -3 H - Imidazolin [5,1-c][1,4] 㗁 𠯤 -2- base ) Benzyl butyrate (compound 15e ）

To a solution of ( 2S )-2-(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[5,1-c][1,4]oxazolidin-2-yl)-3-methyl-butyric acid benzyl ester (Compound 15e , 1 g, 2.89 mmol) in THF (5 mL) was added boron trifluoride etherate (1 M, 1.2 mL, 1.2 mmol) and borane-THF (5.77 mL, 5.77 mmol) at 0°C. After stirring at 20°C for 18 hours, the reaction was quenched with water (40 mL). The aqueous phase was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (60 mL), dried over Mg ₂ SO ₄ , filtered, and concentrated under vacuum to obtain a residue. The residue was purified by reverse phase column to obtain (2 S )-3-methyl-2-(1-oxo-5,6,8,8a-tetrahydro- 3H -imidazo[5,1-c][1,4]oxath-2-yl)butanoic acid benzyl ester (Compound 15f , 220.0 mg) as a colorless oil. MS Calcd. 333.2 (MH ⁺ ), Found 333.2 (MH ⁺ ).

Steps 5 : (2 S )-3- methyl -2-(3- Lateral oxygen -5,6,8,8a- Tetrahydrogen -1 H - Imidazolin [5,1-c][1,4] 㗁 𠯤 -2- base ) Butyric acid (compound 15f ）

To a solution of benzyl ( 2S )-3-methyl-2-(1-oxo-5,6,8,8a-tetrahydro- 3H -imidazo[5,1-c][1,4]oxathian-2-yl)butanoate (compound 15e , 130.0 mg, 0.39 mmol) in THF (1 mL) was added Pd/C (40.0 mg, 0.78 mmol). The reaction mixture was stirred at 25 °C for 1 h under hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to give ( 2S )-3-methyl-2-(3-hydroxy-5,6,8,8a-tetrahydro- 1H -imidazo[5,1-c][1,4]oxath-2-yl)butanoic acid (Compound 15g , 62.0 mg) as a colorless oil. MS Calcd. 243.1 (MH ⁺ ), Found 243.2 (MH ⁺ ).

Examples 16

(3 R )- N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-N -pyridinyl -3- pyridyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4-thia- 9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28), 19,22 (26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ]-3- hydroxy- N ,3- Dimethyl - piperidin -1 -carboxamide

The title compound was prepared similarly to Example 1 by using (3 R )-3-methylpiperidin-3-ol; hydrochloride and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexene-8,14-dione (Intermediate I ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 16 (13.9 mg) was obtained as a white solid. MS calcd. 1042.5 (MH ⁺ ), found 1042.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.73 - 8.69 (d, J = 7.2 Hz, 1H), 8.44 - 8.39 (d, J = 2.8 Hz, 1H), 7.70 - 7.67 (d, J = 2.8 Hz, 1H), 7.67 - 7.64 (d, J = 2.4 Hz, 1H), 7.51 - 7.45 (d, J = 12.4 Hz, 1H), 5.80 - 5.74 (d, J = 8.4 Hz, 1H), 5.23 - 5.13 (m, 1H), 4.83 - 4.76 (m, 1H), 4.47 - 4.40 (m, 1H), 4.29 - 3.74 - 3.69 (d, J = 11.2 Hz, 1H), 3.56 - 3.45 ( m , 2H), 3.39 - 3.36 (m, 6H) , 3.28 - 3.10 (m, 2H), 3.15 - 3.23 (m, 3H), 3.20 - 3.24 (m, 2H), 3.19 - 3.30 (m, 3H), 3.33 - 3.35 (m, 4H), 3.54 - 3.59 (m, 2H), 3.70 - 3.81 (m, 3H), 3.83 - 3.85 (m, 4H), 3.82 - 3.84 (d, J = 11.2 Hz, 1H), 3.03 - 2.96 (d, J = 12.8 Hz, 2H), 2.91 - 2.89 (s, 3H), 2.87 - 2.78 (m, 1H), 2.71 - 2.63 (m, 1H), 2.29 - 2.16 (m, 2H), 2.00 - 1.90 (m, 3H), 1.88 - 1.76 (m, 1H), 1.74 - 1.68 (m, 1H), 1.67 - 1.53 (m, 3H), 1.49 - 1.45 (d, J = 6.4 Hz, 3H), 1.34 - 1.27 (m, 1H), 1.25 - 1.21 (s, 3H), 0.99 - 0.93 (dd, J = 6.0, 12.0 Hz, 9H), 0.56 - 0.49 (s, 3H).

Examples 17

N -[(1 S )-1-[[(7 S ,13 S )-25- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin -1- yl ]-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4 - thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -Methyl - morpholine -4 - carboxamide

The title compound was prepared similarly to Example 1 by using morpholine and ( 7S , 13S )-7-amino-25-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25), ^2,5 (28),19,22( ²⁶ ),23-hexaene-8,14-dione (Intermediate J ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 17 (12.9 mg) was obtained as a yellow solid. MS calcd. 1094.5 (MH ⁺ ), found 1094.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.49 - 8.39 (m, 1H), 7.74 (br s, 1H), 7.53 - 7.44 (m, 3H), 5.97 (br d, J = 5.9 Hz, 1H), 5.18 - 5.11 (m, 1H), 4.67 - 4.58 (m, 1H), 4.42 - 4.33 (m, 1H), 4.10 - 3.97 (m, 1H), 3.94 - 3.80 (m, 2H), 3.76 - 3.63 (m, 5H), 3.58 - 3.42 (m, 7H), 3.26 - 3.14 (m, 8H), 3.13 - δ 5.1 - 5.7 (m, 5H). 3.3 - 3.1 (m, 5H). 1.43 - 1.15 (m, 5H). 3.99 (m, 2H), 2.93 (br d, J = 14.4 Hz, 8H), 2.62 - 2.53 (m, 1H), 2.30 - 2.14 (m, 1H), 1.61 - 1.49 (m, 1H), 1.43 (br d, J = 6.1 Hz, 3H), 1.34 - 1.15 (m, 3H), 0.92 (br t, J = 7.3 Hz, 6H), 0.85 - 0.69 (m, 6H).

Examples 18

N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin -1- yl ]-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4 - thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N ,4- dimethyl - piperidin -1 - carboxamide

The title compound was prepared similarly to Example 1 by using 1-methylpiperidinium and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25), ^2,5 (28), ^19,22 (26),23-hexaene-8,14-dione (Intermediate E ) instead of N , N -dimethyltetrahydroazide-3-amine dihydrochloride (Compound 1D ) and ( 7S , 13S )-7-amino-24-fluoro-( 20M )-20-[2-[( 1S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia- ^9,21,27,28 -tetraazapentacyclo[ ^{17.5.2.12,5.19,13.022,26} ]octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate C ) ^were used to prepare the product. Example 18 (10.8 mg) was obtained as a white solid. MS calcd. 1108.5 (MH ⁺ ), found 1108.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.70 - 8.65 (d, J = 7.6 Hz, 1H), 8.45 - 8.40 (d, J = 2.8 Hz, 1H), 7.70 - 7.65 (d, J = 2.4 Hz, 1H), 7.50 - 7.43 (d, J = 12.8 Hz, 1H), 7.33 - 7.28 (d, J = 2.8 Hz, 1H), 5.78 - 5.70 (d, J = 9.2 Hz, 1H), 5.20 - 5.05 (m, 1H), 4.62 - 4.61 (s, 1H), 4.46 - 4.40 (m, 1H), 4.28 - 9 (m, 3H), 4.20 (m, 1H), 4.19 - 4.21 (m, 1H), 4.08 - 3.99 (d, J = 11.2 Hz, 1H), 3.83 - 3.65 (m, 3H), 3.53 - 3.40 (m, 4H), 3.27 - 3.07 (m, 6H), 2.94 - 2.81 (m, 9H), 2.63 - 2.45 (m, 6H), 2.37-2.34 (s, 3H), 2.29 - 2.17 (m, 3H), 2.00 - 1.93 (m, 1H), 1.90 - 1.75 (m, 2H), 1.71 - 1.56 (m, 1H), 1.46 - 1.41 (d, J = 6.4 Hz, 3H), 1.33 - 1.15 (m, 1H), 0.98 - 0.91 (m, 9H), 0.47 - 0.42 (s, 3H).

Examples 19

N -[(1 S )-1-[[(7 S ,13 S )-24- fluoro- (20 M )-20-[2-[(1 S )-1- methoxyethyl ]-5-[4-(2,2,2 -trifluoroethyl ) piperidin -1- yl ]-3- pyridinyl ]-17,17 -dimethyl -8,14- dioxo -21-(2,2,2 -trifluoroethyl )-15- oxa - 4 - thia -9,21,27,28 -tetraazapentacyclo [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl -1(25),2,5(28),19,22(26),23- hexaen -7- yl ] aminomethyl ]-2- methyl - propyl ] -N -methyl - 4- (2,2,2- trifluoroethyl ) piperidin -1 - carboxamide

Similarly to the preparation of Example 1 , the title compound was prepared by using 1-(2,2,2-trifluoroethyl)piperidinium and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octacosyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate E ) was used to replace N , N -dimethyltetrahydroazir-3-amine dihydrochloride (Compound 1D ) and (7 S ,13 S )-7-amino-24-fluoro-(20 M )-20-[2-[(1 S )-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic [17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate C ). Example 19 (12.1 mg) was obtained as a white solid. MS calculated value 1176.5 (MH ⁺ ), found value 1176.5 (MH ⁺ ). ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.82 - 8.63 (d, J = 7.2 Hz, 1H), 8.48 - 8.38 (d, J = 2.8 Hz, 1H), 7.75 - 7.67 (d, J = 2.0 Hz, 1H), 7.54 - 7.43 (d, J = 12.4 Hz, 1H), 7.35 - 7.28 (d, J = 2.4 Hz, 1H), 5.86 - 5.72 (d, J = 8.8 Hz, 1H), 5.26 - 5.03 (m, 1H), 4.98 - 4.90 (m, 3H), 4.66 - 4.56 (m, 1H), 4.51 - 3.41 (m, 1H), 4.32 - 4.13 (m, 2H), 4.07 - 4.03 (d, J = 11.3 Hz, 1H), 3.86 - 3.77 (d, J = 11.6 Hz, 1H), 3.76 - 3.69 (d, J = 11.2 Hz, 1H), 3.57 - 3.48 (m, 1H), 3.48 - 3.41 (m, 2H), 3.39 - 3.35 (d, J = 3.1 Hz, 4H), 3.29 - 3.23 (m, 1H), 3.22 - 3.10 (m, 6H), 2.96 - 2.92 (s, 3H), 2.91 - 2.86 (t, J = 4.8 Hz, 4H), 2.85 - 2.76 (m, 3H), 2.76 - 2.69 (m, 2H), 2.67 - 2.57 (d, J = 14.4 Hz, 1H), 2.33 - 2.19 (m, 2H), 2.03 - 1.94 (m, 1H), 1.92 - 1.79 (m, 1H), 1.73 - 1.59 (m, 1H), 1.50-1.41 (d, J = 6.0 Hz, 3H), 1.35 - 1.30 (m, 1H), 1.00 - 0.92 (m, 9H), 0.54 - 0.41 (s, 3H).

Biological examples

Compound A555 from WO2021091956 (page 158 of Table 1) is cited as a reference compound of the present invention. (A555)

Examples 20

female BALB/c Single-dose pharmacokinetics in mice (PK) Research

The aim of this study was to determine the pharmacokinetics of selected compounds after single intravenous bolus or oral gavage administration in female BALB/c mice. Briefly, two groups of female BALB/c mice (obtained from Shanghai Lingchang Biotechnology Co., Ltd) (N=3/group) were treated with a single dose of compound at 3 mg/kg (IV) intravenously or 30 mg/kg (PO) orally. Blood samples were collected at 5 min (IV only), 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h after dosing. Blood samples were kept on ice until centrifuged to obtain plasma samples. The concentration of compound in plasma samples was determined using LC-MS/MS method. Pharmacokinetic parameters were calculated by non-compartmental analysis.

Table 1. Results of SDPK Compound 3 mg/kg iv 30 mg/kg, orally CL (mL/min/kg) C _max (ng/mL) AUC _0-last (h×ng/mL) F(%) Example 6 3.70 4889 36825 29.7 A555 42.1 725 2477 21.5

As can be seen from Table 1, Example 6 has excellent pharmacokinetic properties in the mouse model, including an almost 7-fold higher _Cmax and a 15-fold higher AUC0 _-last , as well as improved bioavailability and significantly reduced clearance compared to compound A555.

Examples twenty one

Human hepatocyte stability assay

Hepatocyte stability assays measure the rate of disappearance of compounds following incubation with cryopreserved human hepatocyte suspensions. Positive controls, including midazolam, raloxifene, and dextromethorphan, were included in each experiment. Incubations consisted of 1 μM test compound and human hepatocyte suspensions (1×10 ⁶ cells/mL) in Williams' E medium supplemented with 10% FBS and 0.5% penicillin-streptomycin. Hepatocyte suspensions were incubated at 37°C in a 5% CO ₂ incubator with intermittent shaking at 900 rpm. The reaction was terminated by the addition of methanol containing an internal standard (2 µM tolbutamide) at 2, 10, 20, 40, 60, and 120 min after compound addition, and the consumption of the parent compound was monitored by LC-MS/MS analysis.

surface 2. Human hepatocyte stability of the embodiments and compounds of the present invention Examples CL_hep (human) (ml/min/kg) A555 6.5 Example 6 ＜ 2.4

The above results clearly show that the reference compound ( A555 ) has a much higher clearance rate in the human hepatocyte stability assay, while Example 6 maintains a low clearance rate. Achieving a low clearance rate is beneficial to improving the in vivo performance of the compound, such as dose reduction, exposure enhancement, and half-life extension.

Examples twenty two

Cell viability assay

The purpose of this cellular assay is to measure the effect of test compounds on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL-1739) cells, SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at the endpoint using the Cell Counting Kit-8.

Cells were seeded at 5,000 cells/well (NCI-H358), 2,000 cells/well (AGS), 2,000 cells/well (SW620) in 96-well assay plates (Corning-3699) and incubated overnight. On the day of the assay, diluted compounds were then added at a final concentration of 0.5% DMSO. After 72 hours of incubation, one-tenth the volume of Cell Counting Kit 8 (Dnjindo-CK04) was added to each well. After 2 hours of incubation, the signal was read using EnVision (OD450 minus OD650). _IC50 was determined by fitting a 4-parameter sigmoidal concentration response model.

surface 3. The embodiments and compounds of the present invention are KRAS Activity in cell viability assays Examples G12C IC50 (μM) G12D IC50 (μM) G12V IC50 (μM) A555 0.003 0.008 0.003 Example 1 0.002 0.013 0.001 Example 2 0.004 0.016 0.003 Example 3 0.001 0.015 0.001 Example 4 0.003 0.017 0.001 Example 5 0.002 0.004 0.001 Example 6 0.005 0.020 0.002 Example 8 0.012 0.057 0.007 Example 9 0.024 0.091 0.014 Example 10 0.006 0.040 0.006 Example 11 0.002 0.006 0.001 Example 12 0.009 0.038 0.007 Example 13 0.026 0.447 0.029 Example 14 0.100 ＞10 0.073 Example 15 1.201 1.375 0.064 Example 16 0.016 0.069 0.009 Example 17 0.004 0.046 0.006

Examples twenty three

KRAS-BRAF and CYPA (500 nM) Interaction assay

In this example, TR-FRET was also used to measure compound- or compound-CYPA-dependent disruption of the KRAS G12C-BRAF complex. This approach was also used to measure disruption of KRAS G12D or KRAS G12V binding to BRAF by compounds of the invention, respectively. In assay buffer containing 25mM HEPES pH=7.4 (4-(2-hydroxyethyl)-1-piperidiniumethanesulfonic acid, Thermo, 15630080), 0.002% Tween20, 0.1% BSA, 100mM NaCl, 5mM MgCl ₂ , 10 µM GMPPNP (guanosine 5′-[β,γ-imido] triphosphate trisodium salt hydrate, Sigma, G0635), untagged CYPA, GMPPNP-loaded 6His-KRAS protein and GST-BRAF ^RBD were mixed in the wells of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM and 1 nM, respectively. Compounds were present in the wells in a 16-point 3-fold dilution series starting at a final concentration of 10 µM and incubated for 3 hours. A mixture of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and MAb anti-GST-TB cryptate (Cisbio, 61GSTTLB) was then added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plates were incubated for an additional 1.5 hours. TR-FRET signals were read on a PHERstar FSX microplate reader (Ex320 nm, Em 665/615 nm). Compounds that promoted the disruption of the KRAS-BRAF complex were identified as those that caused a decrease in the TR-FRET ratio relative to the DMSO control wells.

surface 4. The embodiments and compounds of the present invention are KRAS-BRAF and CYPA (500 nM) Activity in interaction assays Examples G12C IC50 (μM) G12D IC50 (μM) G12V IC50 (μM) A555 0.005 0.043 0.023 Example 1 0.046 0.147 0.070 Example 5 0.050 0.089 0.129 Example 6 0.023 0.071 0.061 Example 7 0.095 0.472 0.611 Example 9 0.049 0.225 0.124 Example 10 0.061 0.186 0.149 Example 11 0.024 0.112 0.059 Example 12 0.029 0.140 0.085 Example 13 ＞10 ＞10 ＞10 Example 14 ＞10 ＞10 ＞10 Example 15 0.892 1.648 0.924 Example 16 0.026 0.059 0.097 Example 17 0.002 0.007 0.004

Examples twenty four

pERK Inhibition assay

This assay was used to measure the ability of test compounds to inhibit ERK phosphorylation, downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620. NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL-1739) cells, and SW620 (ATCC-CCL-227) cells were grown and maintained in RPMI-1640 medium (Thermo Fisher Scientific) with 10% fetal bovine serum and 1% penicillin/streptomycin. One day prior to compound addition, cells were plated at 30,000 cells/well, 20,000 cells/well, 30,000 cells/well for NCI-H358, AGS, and SW620, respectively, in tissue culture treated 96-well plates (Corning-3699) and allowed to attach overnight. Diluted compounds were then added at a final concentration of 0.5% DMSO. After 4 hours of incubation, the medium was removed, 100 µL of 4% formaldehyde was added, and the plates were incubated at room temperature for 20 minutes. The plates were then washed once with phosphate-buffered saline (PBS) and permeabilized with 100 µL of ice-cold methanol for 10 minutes. Nonspecific antibody binding to the plates was blocked with 50 µL of 1X BSA blocking buffer (Thermo-37520, 10-fold diluted in phosphate-buffered saline Tween (PBST)) for at least 1 hour at room temperature.

The amount of phospho-ERK was determined using an antibody specific for the phosphorylated form of ERK. The primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, 50 µL was aliquoted to each well and incubated overnight at 4°C. The cells were washed five times with PBST for 5 minutes. The secondary antibody (HRP-linked anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer, 50 µL was added to each well and incubated for 1-2 hours at room temperature. The cells were washed 5 times with PBST for 5 minutes, 100 µL TMB ELISA substrate (abcam-ab171523) was added, and gently shaken for 20 minutes. 50 µL stop solution (abcam-ab171529) was added, and then the signal (OD450) was read by EnVision.

_IC50 was determined by fitting a 4-parameter sigmoidal concentration-response model.

surface 5. The embodiments and compounds of the present invention are KRAS pERK Activity in inhibition assay Examples G12C IC ₅₀ (μM) G12D IC ₅₀ (μM) G12V IC ₅₀ (μM) A555 0.004 0.003 0.003 Example 1 0.001 0.002 0.001 Example 2 0.001 0.005 0.004 Example 3 0.001 0.001 0.001 Example 4 0.001 0.003 0.001 Example 5 0.002 0.002 ＜ 0.001 Example 6 0.002 0.003 0.002 Example 8 0.024 0.024 0.005 Example 9 0.024 0.023 0.009 Example 10 0.014 0.008 0.006 Example 11 0.003 0.001 0.001 Example 12 0.006 0.015 0.004 Example 13 0.019 0.046 0.008 Example 14 0.028 0.032 0.012 Example 15 0.058 0.047 0.031 Example 16 0.013 0.008 0.007 Example 17 0.008 0.004 0.004 Example 18 0.023 0.012 0.007 Example 19 0.066 0.054 0.016

Examples 25

Stable KRAS Mutant cell lines and cell viability assays.

The purpose of this study was to measure the potency and efficacy of compounds on cell proliferation using the CellTiter-Glo® (CTG) luminescent cell viability assay (Promega Corp., Madison, WI). We cloned 14 KRAS ^G12C variant sequences with secondary mutations (V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H, and F156L) into Miapaca-2. A total of 14 stable Miapaca-2 mutant cell lines were established by lentiviral infection. For cell viability assays, compounds were dosed to cells in a 9-point dosing response using a 4-fold dilution series with a top dose of 10 µM. KRAS mutant cells were maintained in DMEM+10%FBS+2.5%HI horse serum+1%PS+1 µg/mL puromycin and seeded in 96-well plates at 800-1,500 cells per well 24 h before compound addition and then incubated with compounds for 3 days before viability assays (CellTiter-Glo, Promega). Assays were performed in biological duplicates. Nonlinear regression curves were fit using Xfit. IC50 (absolute IC50) is the dose at which the estimated viability is 50% relative to untreated wells. The inhibition rate of the compound was calculated as follows: % inhibition = 100-100×(luminescence value-HPE)/(ZPE-HPE).

HPE: Luminescence value from wells with culture medium only

ZPE: Luminescence from wells with DMSO

surface 8 have KRAS G12C Cell viability in mutant cells with other mutations G12C+ V8A, IC50 (μM) G12C+ V9Y, IC50 (μM) G12C+ S17E, IC50 (μM) G12C+ A59T, IC50 (μM) G12C+ T58I, IC50 (μM) G12C+ D60P, IC50 (μM) G12C+ S65W, IC50 (μM) G12C+ R68S, IC50 (μM) G12C+ M72I, IC50 (μM) G12C+ D92R, IC50 (μM) G12C+ H95N, IC50 (μM) G12C+ Y96D, IC50 (μM) G12C+ Q99W, IC50 (μM) G12C+ F156L, IC50 (μM) Example 6 0.002 0.002 0.005 0.011 0.007 0.008 0.006 0.034 0.003 0.005 0.005 0.007 0.007 0.008

Figure 1. X-ray crystallographic analysis of compound G5.

Claims (37)

A compound of formula (I), (I), wherein R ¹ is , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidinyl or (C _1-6 alkyl)oximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridine, C _1-6 alkylpiperidinyl, halogen tetrahydroaziridine, halogen C _1-6 alkylamino, halogen C _{1-6 alkylaminotetrahydroaziridine, halogen C 1-6} alkylpiperidinyl _, hydroxy(C _1-6 alkyl)piperidinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is fluoroquinoline, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ^{1 is} thiazolyl; A ² is C _1-6 alkyl; provided that R ₃ and R ⁴ are not H at the same time; or a pharmaceutically acceptable salt _thereof . A compound of formula (Ia), (Ia), wherein R ¹ is , 3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazolidinyl or (C _1-6 alkyl)oximidazolidinyl; wherein R ⁸ is C _1-6 alkyl; R ⁹ is ((C _1-6 alkyl) _2amino )tetrahydroaziridine, C _1-6 alkylpiperidinyl, halogen tetrahydroaziridine, halogen C _1-6 alkylamino, halogen C _{1-6 alkylaminotetrahydroaziridine, halogen C 1-6} alkylpiperidinyl _{, hydroxy(C 1-6 alkyl)piperidinyl or morpholinyl; R 2 is C 1-6 alkyl} ^; _R ³ is H or halogen; R ⁴ is H or halogen; R ⁵ is C R ⁶ is C _1-6 alkoxy C _{1-6 alkyl} ; R ⁷ is fluoroquinoline, (halogenated C _1-6 alkyl)piperidinyl or C _1-6 alkylpiperidinyl; A ¹ is thiazolyl; A ² is C _1-6 alkylene; provided that R ³ and R ⁴ are not H at the _same time; or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein R ¹ is ; wherein R ⁸ is C _1-6 alkyl; R ⁹ is C _1-6 alkylpiperidinyl, halogen C _1-6 alkylpiperidinyl or morpholinyl. The compound of any one of claims 1 to 3, wherein R ¹ is ; wherein R ⁸ is methyl; R ⁹ is 4-methylpiperidin-1-yl, 4-(2,2,2-trifluoroethyl)piperidin-1-yl or morpholinyl. The compound of any one of claims 1 to 4, wherein R ¹ is methyl-(4-methylpiperidin-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperidin-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino. The compound of any one of claims 1 to 5, wherein R ² is isopropyl. The compound of any one of claims 1 to 6, wherein R ³ is H or fluorine. The compound of any one of claims 1 to 7, wherein R ³ is fluoro. The compound of any one of claims 1 to 8, wherein R ⁴ is H or fluorine. The compound of any one of claims 1 to 9, wherein R ⁴ is H. The compound of any one of claims 1 to 10, wherein R ⁵ is halogen C _1-6 alkyl. The compound of any one of claims 1 to 11, wherein R ⁵ is 2,2,2-trifluoroethyl. The compound of any one of claims 1 to 12, wherein R ⁶ is 1-methoxyethyl. The compound of any one of claims 1 to 13, wherein R ⁷ is (halogen C _1-6 alkyl)piperidinyl. The compound of any one of claims 1 to 14, wherein R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl. The compound of any one of claims 1 to 15, wherein ^A1 is , where bond "a" is attached to the indole ring. A compound as claimed in any one of claims 1 to 16, wherein A ² is dimethylmethylene. The compound of claim 1 or 2, wherein R ¹ is wherein R ⁸ is C _1-6 alkyl; R ⁹ is C _1-6 alkylpiperidinyl, halogen C _1-6 alkylpiperidinyl or morpholinyl; R ² is C _1-6 alkyl; R ³ is halogen; R ⁴ is H; R ⁵ is halogen C _1-6 alkyl; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is (halogen C _1-6 alkyl)piperidinyl; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is a _C1-6 alkylene group; or a pharmaceutically acceptable salt thereof. The compound of claim 18, wherein R ¹ is methyl-(4-methylpiperidin-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl)piperidin-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino; R ² is isopropyl; R ³ is fluorine; R ⁴ is H; R ⁵ is 2,2,2-trifluoroethyl; R ⁶ is (1S)-1-methoxyethyl; R ⁷ is 4-(2,2,2-trifluoroethyl)piperidin-1-yl; A ¹ is , wherein bond "a" is connected to the indole ring; ^A2 is dimethylmethylene; or a pharmaceutically acceptable salt thereof. A compound selected from: 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-tetrahydroazol-1-carboxamide; 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-tetrahydroazol-1-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholin-4-carboxamide; 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-tetrahydroazol-1-carboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholin-4-carboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-3,3-difluoro-N-methyl-tetrahydroazol-1-carboxamide; (2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(3-methyl-2-oxo-imidazolidin-1-yl)butyramide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperidin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholin-4-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-20-(20M)-[2-[(1S)-1-methoxyethyl]-5-N-morpholinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-tetrahydroazol-1-carboxamide; (2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-[methyl(2,2,2-trifluoroethylaminomethyl)amino]butyramide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-3-(trifluoromethyl)tetrahydroazol-1-carboxamide; (2S)-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxadiazol-2-yl)butyramide; (3R)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-N-oxolinyl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminocarbonyl]-2-methyl-propyl]-3-hydroxy-N,3-dimethyl-piperidin-1-carboxamide; N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ] octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminomethyl]-2-methyl-propyl]-N,4-dimethyl-piperidin-1-carboxamide; and N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperidin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxo-4-thia-9,21,27,28-tetraazapentacyclic[17.5.2.1 ^2,5 .1 ^9,13 .0 ^22,26 ]octadecyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]aminocarbonyl]-2-methyl-propyl]-N-methyl-4-(2,2,2-trifluoroethyl)piperidin-1-carboxamide; or a pharmaceutically acceptable salt thereof. A method for preparing a compound as claimed in any one of claims 1 to 20, comprising the following steps: a) in the presence of a coupling reagent and a base, reacting a compound of formula (II), (II) and acid (III), (III) to form a compound of formula (I); wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A ¹ and A ² are as defined in any one of claims 1 to 19; the coupling reagent is T ₃ P, HATU, PyBOP or EDCI/HOBt; the base is TEA, DIEPA or DMAP. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 20 for use as a therapeutically active substance. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient. A use of the compound of any one of claims 1 to 20 for treating a KRAS G12C protein-related disease. A use of a compound according to any one of claims 1 to 20 for treating diseases associated with KRAS G12C, G12D and G12V proteins. A use of the compound of any one of claims 1 to 20 for inhibiting the interaction between RAS and downstream effectors, wherein the downstream effectors are RAF and PI3K. A use of a compound according to any one of claims 1 to 20 for inhibiting propagation of oncogenic MAPK and PI3K signaling. A use of a compound according to any one of claims 1 to 20 for treating or preventing a cancer driven by a KRAS mutation, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer. A use of a compound according to any one of claims 1 to 20 for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 20, for use in treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer. A use of a compound of any one of claims 1 to 20 for treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation of G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L. A use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer. A use of a compound as claimed in any one of claims 1 to 18 for the preparation of a medicament for treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation of G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H and F156L. A method for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 20. A method of treating or preventing a KRAS mutation-driven cancer, wherein the cancer comprises a first mutation that is G12C and a second mutation at a position selected from V8A, V9Y, S17E, T58I, A59T, S65W, R68S, D69P, M72I, D92R, H95N, Y96D, Q99F, Q99W, Y96H, and F156L. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 20, manufactured by the method of claim 21. The present invention as described above.